Spatial and Temporal Progression of Neurodegeneration in Confirmed and Suspected TDP-43 Type C Pathology

Abstract

The delineation of disease progression in neurodegenerative entities offers neurobiological insights into pathophysiology as well as practical information on natural progression that can be used to gauge the benefits of treatment. In AD, FTLD-tau and FTLD-TDP types A and B such advances have been achieved based on the investigation of presymptomatic mutation carriers. In the absence of dominant mutations, this approach is not feasible in FTLD-TDP type C (TDP-C). Considering the subtlety of the initial symptoms, it is almost certain that the disease had been progressing for years before the first investigations are obtained. We addressed this limitation through an indirect approach based on the fact that neurodegeneration in TDP-C can be asymmetric for 5-6 years after symptom onset. In time, the contralateral hemisphere starts to show the onset of atrophy, the spread of which mirrors the pattern in the affected hemisphere. The unaffected hemisphere therefore offers an opportunity for capturing the very first emergence of atrophy. To that end, we traced the onset and progression of neurodegeneration in TDP-C by analyzing the right hemisphere longitudinally in cases of asymmetric left anterior temporal atrophy. In these cases, TDP-C was either confirmed at autopsy or suspected based on the clinical features and anatomy of atrophy. Structural MRIs were processed using voxel-based morphometry and parcellated into cortical and subcortical regions. W-scores were computed to identify volume loss relative to age-matched controls. Linear mixed-effects models assessed disease progression across regions of interest (ROIs). Results of our analyses reveal that atrophy in TDP-C follows a stereotyped progression within the right hemisphere, beginning in the ventromedial anterior temporal lobe and extending posteriorly and laterally over time. Early atrophy was most prominent in the medial temporal pole (planum polare), perirhinal cortex, entorhinal cortex, and anterior fusiform cortex, with subcortical involvement initially limited to the amygdala. Voxelwise and ROI-based analyses confirmed that cortical atrophy preceded and exceeded amygdala atrophy in most cases, suggesting greater neocortical vulnerability. Longitudinal linear mixed-effects models identified the greatest volume loss in medial temporal ROIs and the amygdala, following a consistent anterior-to-posterior gradient over time. These findings reconstruct the spatial and temporal progression of TDP-C pathology using the initially unaffected hemisphere as a proxy for early disease stages. The stereotyped trajectory of atrophy aligns with neuropathological patterns and offers critical insights into disease progression, aiding therapeutic evaluation.

Keywords: MRI; Neurodegeneration; TDP-43; atrophy; longitudinal; primary progressive aphasia.

Fig. 1.

Percentage of Participants with Brain Volume W-Scores Below -1.5 in Right Hemisphere Regions of Interest (ROIs) at Visits A, B, and C This figure illustrates the percentage of participants with brain volume W-scores below -1.5, based on comparison to normal controls, in 180 right hemisphere ROIs derived from the Glasser et al. (2016) HCP-MMP atlas for visits A, B, and C. Subcortical regions are parcellated according to the Tian et al. (2020) atlas; labels are intended to aid interpretability and do not reflect definitive subregional boundaries. Visualizations are thresholded at 25%, displaying ROIs where 25% or more participants fall below the W-score threshold across the three visits. PRC = perirhinal cortex, EC = entorhinal cortex, aFG = anterior fusiform gyrus, PHA = parahippocampal area, PreS = presubiculum, pTG/VWFA = posterior temporal gyrus/visual word form area, midFG = middle fusiform gyrus, midMTG/ITG = middle and inferior temporal gyri, aMTG/ITG = anterior middle and inferior temporal gyri, pSTG/STS = posterior superior temporal gyrus and superior temporal sulcus, TPR = temporal pole region, Pir = piriform cortex, Ins = insula, and IFGorb = orbital portion of the inferior frontal gyrus. l/m-AMY = lateral and medial amygdala.

Fig. 2.

High Threshold Percentage of Participants with Brain Volume W-Scores Below -1.5 Visualized Voxelwise in the Right Hemisphere at Visit A. This figure presents voxelwise visualizations of the percentage of participants with brain volume W-scores below -1.5, in the right hemisphere, for visit A only. Data are thresholded at 80%, with axial slices showing areas where 80% or more participants fall below the W-score threshold. Figure labels based on Mai et al. (2015); labels are intended to aid interpretability and do not reflect definitive subregional boundaries. Ppo = Planum polare, ITP = Inferior temporopolar region, STG = Superior temporal gyrus, MTG = Middle temporal gyrus, Pir = Piriform Cortex, Ent = Entorhinal cortex, PRC = perirhinal cortex, AMY = amygdala, FuG = fusiform gyrus.

Fig. 3.

Percentage of Participants with Brain Volume W-Scores Below -1.5 Visualized Voxelwise in the Right Hemisphere at Visits A, B, and C. This figure presents voxelwise visualizations of the percentage of participants with brain volume W-scores below -1.5, compared to normal controls, in the right hemisphere, for visits A, B, and C. Data are thresholded at 25%, with axial slices showing areas where 25% or more participants fall below the W-score threshold. The voxelwise analysis provides detailed insight into specific regions of interest across the right hemisphere. Figure labels based on Mai et al. (2015); labels are intended to aid interpretability and do not reflect definitive subregional boundaries. Ppo = Planum polare, ITP = Inferior temporopolar region, STG = Superior temporal gyrus, MTG = Middle temporal gyrus, ITG = Inferior temporal gyrus, Pir = Piriform Cortex, Ent = Entorhinal cortex, PAM = periamygdaloid complex, AMY = amygdala, FuG = fusiform gyrus, HIH = hippocampal head, DG = dentate gyrus.

Fig. 4.

Effects of Years Since Symptom Onset on Brain Volume. This figure displays the results of linear mixed-effects models examining the effect of disease duration on brain volume across 180 right-hemisphere regions of interest (ROIs) from the Glasser et al. (2016) HCP-MMP atlas and 16 subcortical ROIs from Tian et al. (2020); labels are intended to aid interpretability and do not reflect definitive subregional boundaries. Lighter yellow values correspond to faster rates of volume loss per year since symptom onset. The colorbar is thresholded to display only ROIs exceeding a stringent FDR-corrected significance level. PRC = perirhinal cortex, EC = entorhinal cortex, aFG = anterior fusiform gyrus, PHA = parahippocampal area, PreS = presubiculum, pTG/VWFA = posterior temporal gyrus/visual word form area, midFG = middle fusiform gyrus, midMTG/ITG = middle and inferior temporal gyri, aMTG/ITG = anterior middle and inferior temporal gyri, pSTG/STS = posterior superior temporal gyrus and superior temporal sulcus, TPR = temporal pole region, Pir = piriform cortex, Ins = insula, and IFGorb = orbital portion of the inferior frontal gyrus.