Frontotemporal Degeneration with Transactive Response DNA-Binding Protein Type C at the Anterior Temporal Lobe

Abstract

The anatomical distribution of most neurodegenerative diseases shows considerable interindividual variations. In contrast, frontotemporal lobar degeneration with transactive response DNA-binding protein type C (TDP-C) shows a consistent predilection for the anterior temporal lobe (ATL). The relatively selective atrophy of ATL in TDP-C patients has highlighted the importance of this region for complex cognitive and behavioral functions. This review includes observations on 28 TDP-C patients, 18 with semantic primary progressive aphasia and 10 with other syndromes. Longitudinal imaging allowed the delineation of progression trajectories. At post-mortem examination, the pathognomonic feature of TDP-C consisted of long, thick neurites found predominantly in superficial cortical layers. These neurites may represent dystrophic apical dendrites of layer III and V pyramidal neurons that are known to play pivotal roles in complex cortical computations. Other types of frontotemporal lobar degeneration TDP, such as TDP-A and TDP-B, are not associated with long dystrophic neurites in the cerebral cortex, and do not show similar predilection patterns for ATL. Research is beginning to identify molecular, structural, and immunological differences between pathological TDP-43 in TDP-C versus TDP-A and B. Parallel investigations based on proteomics, somatic mutations, and genome-wide association studies are detecting molecular features that could conceivably mediate the selective vulnerability of ATL to TDP-C. Future work will focus on characterizing the distinctive features of the abnormal TDP-C neurites, the mechanisms of neurotoxicity, initial cellular targets within the ATL, trajectory of spread, and the nature of ATL-specific markers that modulate vulnerability to TDP-C. ANN NEUROL 2023;94:1-12.

Figure 1.. Selectivity of TDP-C for ATL Shown by Free Surfer and at Autopsy.

All images are from a semantic PPA patient (right-handed woman) with symptom onset at the age of 59 and TDP-C at autopsy. Significant atrophy on the cortical surface in A and B is shown by the colored areas, at the false discovery rate of 0.05 using the Free Surfer tool kit. A. Atrophy is confined to left ATL and is sufficient to cause severe and isolated impairment of word comprehension and object naming. B. Four years later all significant atrophy is still confined to ATL but has also emerged on the right. Object naming further decreased and non-verbal object recognition started to fail, likely due to bilaterality of ATL atrophy. C. Autopsy specimen of the patient 12 years after symptom onset. The macroscopic neurodegeneration is still strongly selective for ATL. Abbreviations: ATL-anterior temporal lobe; E- entorhinal/perirhinal cortex; F-fusiform gyrus; FP- frontal pole; I-inferior temporal gyrus; M- middle temporal gyrus; OFC- orbitofrontal cortex; OP-occipital pole; TP- temporal pole.

Figure 2.. Progression of Gyral and Sulcal Peak Atrophy Sites Shown by Voxel Based Morphometry.

The colored patches on rows A and B indicate areas of cortical volume loss in comparison to a control group at a statistical significance of p<.001 and minimum cluster size of 100 voxels. These are peak atrophy sites. The presence of additional atrophy that fails to reach statistical significance cannot be ruled out. From left to right, each row represents increasingly more caudal coronal sections from the same hemisphere. The mm designations refer to the distance from the anterior commissure (AC) in millimeters, positive numbers indicating locations in front of the AC. A. and B. Left hemisphere of a semantic PPA patient initially seen at an earlier stage of clinical severity than the patient in Figure 1. Images were obtained at an interval of 4 years and represent early (A) and moderate (B) symptomatic stages of neurodegeneration. C. Composite illustration of progressive atrophy. The stage of ‘initial a peak trophy’ is inferred based on emergent right ATL atrophy in PPA patients who had no such atrophy at prior imaging. The progression illustrated in C is approximated to occur over a span of 6–8 years from symptom onset and is based on the examination of 56 hemispheres of the 28 patients with TDP-C, many with longitudinal imaging. The arrows point to the Brodmann areas where initial peak atrophy emerges in our collection of cases. Abbreviations: A- amygdala; AC- anterior commissure; ATL- anterior temporal lobe; BA- Brodmann area; C- caudate; E- entorhinal cortex; F- fusiform gyrus; H- hippocampus; I- inferior temporal gyrus; IFG- inferior frontal gyrus (Broca’s); In- insula; M- middle temporal gyrus; P- perirhinal area; Pu- putamen; S- superior temporal gyrus; T- thalamus.

Figure 3.. MRI Appearance of TDP-C Progression Illustrated by Individual Cases.

A. Distribution of atrophy at an early symptomatic stage. From a TDP-C semantic PPA patient (right-handed man) with onset at the age of 59. Significant atrophy is confined to the part of the left anterior temporal lobe (ATL) located ahead of the limen insulae. The amygdala, rhinal cortices, the fusiform gyrus, and lateral parts of temporal cortex are relatively preserved. B. Intermediate stage of atrophy from a right-handed woman with symptom onset at 59 (same patient shown in Figure 1). Atrophy of the left ATL has become more extensive. The amygdala has mild atrophy, rhinal cortices are severely thinned, the anteriormost part of the fusiform gyrus has been replaced by cerebrospinal fluid (*), and the temporal horn shows ex vacuo enlargement. C. A more advanced stage of atrophy. There is further neurodegeneration in left ATL, amygdala, rhinal cortices and the fusiform gyrus. Atrophy has now spread to the lateral temporal cortices (T). Abbreviations: A- amygdala; ATL- anterior temporal lobe; E- entorhinal/perirhinal areas; F- fusiform gyrus; T- lateral temporal cortices.

Figure 4.. TDP-C Neuropathology.

TDP-43 immunohistochemistry counterstained with cresyl violet from the autopsy of a semantic PPA case with symptom onset at the age of 63 and death 10 years later. A. From the right inferior parietal lobule which was relatively spared. Neuronal architecture is mostly preserved. There is a high density of thick, long, dystrophic neurites pathognomonic of TDP-C, many of which have a rectilinear orientation perpendicular to the cortical surface in an orientation consistent with apical dendrites of pyramidal neurons (double arrowhead). Others are wispy and undulating, reminiscent of interneuron dendrites (single arrowhead). B. Same method showing the left ATL, which had advanced neurodegeneration. There is severe gliosis and loss of neurons. The density of dystrophic neurites is much lower than in the inferior parietal lobule.