Plasma TDP-43 levels are associated with neuroimaging measures of brain structure in limbic regions

Abstract

Introduction: We evaluated the relationship between plasma levels of transactive response DNA binding protein of 43 kDa (TDP-43) and neuroimaging (magnetic resonance imaging [MRI]) measures of brain structure in aging.

Methods: Plasma samples were collected from 72 non-demented older adults (age range 60-94 years) in the University of Kentucky Alzheimer's Disease Research Center cohort. Multivariate linear regression models were run with plasma TDP-43 level as the predictor variable and brain structure (volumetric or cortical thickness) measurements as the dependent variable. Covariates included age, sex, intracranial volume, and plasma markers of Alzheimer's disease neuropathological change (ADNC).

Results: Negative associations were observed between plasma TDP-43 level and both the volume of the entorhinal cortex, and cortical thickness in the cingulate/parahippocampal gyrus, after controlling for ADNC plasma markers.

Discussion: Plasma TDP-43 levels may be directly associated with structural MRI measures. Plasma TDP-43 assays may prove useful in clinical trial stratification.

Highlights: Plasma transactive response DNA binding protein of 43 kDa (TDP-43) levels were associated with entorhinal cortex volume.Biomarkers of TDP-43 and Alzheimer's disease neuropathologic change (ADNC) may help distinguish limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) from ADNC.A comprehensive biomarker kit could aid enrollment in LATE-NC clinical trials.

Keywords: aging; biomarker; cortical thickness; entorhinal cortex; limbic‐predominant age‐related TDP‐43 encephalopathy; neuroimaging; plasma transactive response DNA binding protein of 43 kDa.

FIGURE 1

Association between plasma TDP‐43 levels and ERC volume. The figure displays the ERC ROI mask on a representative participant from this study (A; red) and a scatterplot displaying plasma TDP‐43 levels against ERC volume (B). There was a significant negative association between plasma TDP‐43 level and ERC volume after controlling for age, sex, and ICV. Furthermore, a median split (C) was used to divide participants shown in (B) into low plasma Aβ42/Aβ40 ratio (red circles) and high plasma Aβ42/Aβ40 ratio (blue circles) groups to help identify those individuals at high risk for “pure” LATE‐NC versus those at high risk for mixed pathologies of LATE‐NC + ADNC (C). Participants in the bottom right quadrant (within the black oval) had both high plasma TDP‐43 levels and low ERC volume. While most of these participants had a low plasma Aβ42/Aβ40 ratio (red circles: high risk for both ADNC + LATE‐NC), a small subgroup had a high plasma Aβ42/Aβ40 ratio (blue circles: low ADNC risk, high risk for “pure” LATE‐NC). Aβ, amyloid beta; ADNC, Alzheimer's disease neuropathologic change; ERC, entorhinal cortex; ICV, intracranial volume; LATE‐NC, limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change; ROI, region of interest; TDP‐43, tar DNA binding protein of 43 kDa.

FIGURE 2

Relationship between plasma TDP‐43 level and cortical thickness. Plasma TDP‐43 level was negatively associated with cortical thickness in the left inferior/ventral temporal areas and in the left inferior parietal lobe (A; blue regions). However, after controlling for plasma Aβ42/Aβ40 ratio values, plasma TDP‐43 level was only negatively associated with cortical thickness in the left inferior isthmus of the cingulate/parahippocampal gyrus (B; blue). Aβ, amyloid beta; TDP‐43, tar DNA binding protein of 43 kDa.

FIGURE 3

A schematic summarizing the potential implications of our results for future clinical trials. Our results suggest that integrating TDP‐43 values and ERC volume within the ATN framework could aid in the differentiation of those at high risk for “pure” ADNC and those at risk for “pure” LATE‐NC. Further validation of fluid biomarkers of TDP‐43 will be necessary to ensure accurate quantification of TDP‐43 levels in vivo. ADNC, Alzheimer's disease neuropathologic change; CVD, cerebrovascular disease; ERC, entorhinal cortex; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; LATE‐NC, limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change; MRI, magnetic resonance imaging; ROI, region of interest; TDP‐43, tar DNA binding protein of 43 kDa.