Cortical and subcortical pathological burden and neuronal loss in an autopsy series of FTLD-TDP-type C

Abstract

The TDP-43 type C pathological form of frontotemporal lobar degeneration is characterized by the presence of immunoreactive TDP-43 short and long dystrophic neurites, neuronal cytoplasmic inclusions, neuronal loss and gliosis and the absence of neuronal intranuclear inclusions. Frontotemporal lobar degeneration-TDP-type C cases are commonly associated with the semantic variant of primary progressive aphasia or behavioural variant frontotemporal dementia. Here, we provide detailed characterization of regional distributions of pathological TDP-43 and neuronal loss and gliosis in cortical and subcortical regions in 10 TDP-type C cases and investigate the relationship between inclusions and neuronal loss and gliosis. Specimens were obtained from the first 10 TDP-type C cases accessioned from the Northwestern Alzheimer's Disease Research Center (semantic variant of primary progressive aphasia, n = 7; behavioural variant frontotemporal dementia, n = 3). A total of 42 cortical (majority bilateral) and subcortical regions were immunostained with a phosphorylated TDP-43 antibody and/or stained with haematoxylin-eosin. Regions were evaluated for atrophy, and for long dystrophic neurites, short dystrophic neurites, neuronal cytoplasmic inclusions, and neuronal loss and gliosis using a semiquantitative 5-point scale. We calculated a 'neuron-to-inclusion' score (TDP-type C mean score - neuronal loss and gliosis mean score) for each region per case to assess the relationship between TDP-type C inclusions and neuronal loss and gliosis. Primary progressive aphasia cases demonstrated leftward asymmetry of cortical atrophy consistent with the aphasic phenotype. We also observed abundant inclusions and neurodegeneration in both cortical and subcortical regions, with certain subcortical regions emerging as particularly vulnerable to dystrophic neurites (e.g. amygdala, caudate and putamen). Interestingly, linear mixed models showed that regions with lowest TDP-type C pathology had high neuronal dropout, and conversely, regions with abundant pathology displayed relatively preserved neuronal densities (P < 0.05). This inverse relationship between the extent of TDP-positive inclusions and neuronal loss may reflect a process whereby inclusions disappear as their associated neurons are lost. Together, these findings offer insight into the putative substrates of neurodegeneration in unique dementia syndromes.

Keywords: TDP-43; behavioural variant frontotemporal dementia; frontotemporal lobar degeneration; primary progressive aphasia.

Figure 1

Cortical atrophy and TDP-43 immunoreactive pathology in FTLD-TDP-type C cases. Cortical atrophy of FTLD-TDP-type C is distinct in its selective and severe targeting of the temporal poles (arrows), seen in Case 3, a 71-year-old female with a 15-year duration of the semantic form of primary progressive aphasia (PPA-S), more severe on the left (A). Distribution of TDP-43-positive inclusions varied according to inclusion morphology and type (NCIs, short DNs, long DNs), suggesting that certain neuronal populations may be differentially vulnerable in TDP-type C. TDP-43-positive NCIs were severe in the dentate granular cells of hippocampus (B) and in the striatum (C), and mild in the middle frontal cortex (D). Short DNs were severe in the superior temporal cortex (E) and amygdala (F), and mild in the striatum (G). Long DNs were severe in the superior temporal cortex (H) and mild in the red nucleus (I). (B and H) Case 8; (C) Case 7; (D, E and I) Case 10; (F) Case 1; (G) Case 6. Scale bar = 50 μm in I, and also applies to B–H.

Figure 2

Heat maps of TDP-type C inclusions (NCIs, short DNs, and long DNs) and neuronal loss and gliosis in 10 cases. Each colour block indicates the severity of the disease burden according to the semiquantitative rating scale; 0 = absent, 1 = rare, 2 = mild, 3 = moderate, and 4 = severe; grey shading indicates that the region was not available for pathological inspection. Heat maps were arranged by the highest to lowest average score across all 10 cases for each inclusion type or NL/G. At the group level, we observed an overall positive correlation (Spearman) across all regions between NL/G and NCIs (r = 0.654, P < 0.0001), short DNs (r = 0.662, P < 0.0001) and long DNs (r = 0.537, P < 0.001).

Figure 3

Mean cortical distribution (lateral view) and mean subcortical/cortical distribution (coronal view) of long DNs and NL/G in TDP-type C. Cortical and subcortical distribution maps depict the relationship between TDP-type C long dystrophic neurites (long DNs) and neuronal loss and gliosis at the group level (n = 10). Semiquantitative ratings for (A and B) long DNs and (C and D) NL/G in cortical regions were averaged across all 10 cases. Scale bar on the bottom shows the colour associated with mean scores. Through the anatomic depiction of long DN and NL/G distribution, we found areas that showed an inverse relationship between long DNs and NL/G that was not appreciated through standard heat maps. These areas included the right and left temporal poles, the entorhinal and transentorhinal cortices and the amygdala, which are three regions that are first affected in FTLD-TDP-type C disease progression. (A and C) CBL = cerebellum; IFG = inferior frontal gyrus; IPL = inferior parietal lobule; LH = left hemisphere; MFG = middle frontal gyrus; OCC = occipital; RH = right hemisphere; STG = superior temporal gyrus; TP = temporal pole. (B and D) cd = caudate; cg = cingulate gyrus; cls = claustrum; dg = dentate gyrus; erc = entorhinal cortex; gp = globus pallidus; ic = internal capsule; ins = insula; itg = inferior temporal gyrus; LH = left hemisphere; mc = motor cortex; mtg = middle temporal gyrus; pon = pons; pre-sub = pre-subiculum; pt = putamen; RH = hemisphere; rn = red nucleus; sc = somatosensory cortex; sn = substantia nigra; stg = superior temporal gyrus; stn = subthalamic nucleus; sub = subiculum; th = thalamus; trs erc = transentorhinal cortex. *Refer to Fig. 2 to view NL/G and long DN distribution within the amygdala. Created with BioRender.com.

Figure 4

Relationship between TDP-type C inclusions and NL/G at the individual case level. Neuron-to-inclusion scores were calculated for (A) NCIs, (B) short DNs and (C) long DNs in the selected regions in the high and low neuronal dropout groups, and scores from all 10 cases were plotted. When scores were available from homotypic regions in both hemispheres, such as inferior frontal gyrus (IFG) and temporal poles, scores were averaged for the individual inclusion and NL/G in the right and left hemispheres and used in the analysis and are thus notated as bilateral temporal poles and bilateral IFG. Entorhinal and transentorhinal cortices also had similar neuron-to-inclusion scores and were therefore also averaged, notated as Trans/ERC. Neuron-to-inclusion scores differed significantly between high and low neuronal dropout regions at an individual level across NCIs (P < 0.0001), short DNs (P < 0.0001) and long DNs (P < 0.0001).

Figure 5

Relationship between TDP-type C long DNs, short DNs and NCI in high versus low neuronal dropout at the group level. Neuron-to-inclusion scores were averaged across all 10 cases for long DNs, short DNs and NCIs in the regions designated as part of the high neuronal dropout group and low neuronal dropout group. We found that the median neuron-to-inclusion scores differed significantly (P < 0.05) between these two groups.

Figure 6

Inverse relationship between TDP-type C DNs and NL/G in temporal pole (TP) and middle frontal gyrus (MFG). (B and C) Images were obtained from Case 4, a 55-year-old male with a 10-year duration of the semantic form of primary progressive aphasia (PPA-S). (A) Image was obtained from Case 1, a 74-year-old female with a 12-year duration of PPA-S. (D) Image was obtained from Case 8, a 61-year-old female with an 11-year duration of PPA-S. In the left temporal pole, severe neuronal loss and gliosis are observed (score = 4) (A), with mild-to-moderate TDP-type C pathology (score = 2.5) (C), suggesting that inclusions may wane as neuronal dropout occurs. This is juxtaposed with B and D, which highlight the reverse relationships; in the left MFG, NL/G (B) was mild (score = 1), while the presence of TDP-type C inclusions (D) were severe (score = 4). Scale bar = 50 µm in D, and also applies to A–C.