Plasma TDP‐43 Levels are Associated with Neuroimaging Measures of Temporal Lobe Structure

Abstract

AbstractBackgroundTar DNA binding protein of 43kDa (TDP‐43) proteinopathy is a pathological hallmark of limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), with or without comorbid Alzheimer’s disease neuropathologic change (AD‐NC). At present, the diagnosis of LATE neuropathologic change (LATE‐NC) can only be made at autopsy. There is thus an urgent need for a clinical biomarker for LATE and a blood‐based method would be optimal for clinical and economic reasons. Here, we assessed the relationship between plasma TDP‐43 levels with imaging measures of neurodegeneration (volume and cortical thickness).MethodParticipants were 72 nondemented older adults (47 women, age range 60‐94 years). Immunoassays for TDP‐43, phosphorylated threonine‐181 tau (p‐tau181), total tau (t‐tau), amyloid beta‐42 (Aß42), and amyloid beta‐40 (Aß40) were quantified (pg/mL) in duplicate for each participant using the Quanterix Simoa HD‐X instrument. Neuroimaging was conducted using a 3 Tesla MRI Siemens Prisma scanner with a 64‐channel head coil. A T1‐weighted MPRAGE sequence with 1 cubic mm voxels covering the entire brain was acquired. FreeSurfer software was used to estimate intracranial volume (ICV) and volumes of the entorhinal cortex (ERC), amygdala, and subiculum of the hippocampus, regions known to harbor TDP‐43 pathology in early stages of LATE‐NC. Multivariate linear regression models controlling for age, sex, and ICV were conducted in SPSS using plasma TDP‐43 as the predictor and volumetric or cortical thickness measurements as dependent variables.ResultThere was a negative association between plasma TDP‐43 concentration and ERC volume, a relationship that remained significant after controlling for plasma markers of AD‐NC (the Aß42/Aß40 ratio, p‐tau181/Aß40 ratio or t‐tau/Aß40 ratio). Results from subsequent exploratory analyses indicated a negative association between TDP‐43 and cortical thickness in the inferior temporal lobe, a finding which also remained significant after controlling for AD‐NC plasma biomarkers.ConclusionHigh plasma TDP‐43 levels were associated with in vivo imaging measures of neurodegeneration in multiple temporal lobe structures. Plasma TDP‐43 assays may prove useful in clinical trials seeking to enroll individuals at risk for LATE‐NC.