Clinical Significance of TDP-43 Neuropathology in Amyotrophic Lateral Sclerosis - PubMed (original) (raw)

Clinical Significance of TDP-43 Neuropathology in Amyotrophic Lateral Sclerosis

Matthew D Cykowski et al. J Neuropathol Exp Neurol. 2017.

Abstract

To determine the significance of TAR DNA binding protein 43 kDa (TDP-43) pathology in amyotrophic lateral sclerosis (ALS), we examined the whole brains and spinal cords of 57 patients (35 men; 22 women; mean age 63.3 years; 15 patients with c9orf72-associated ALS [c9ALS]). TDP-43 pathologic burden was determined relative to symptom onset site, disease duration, progression rate, cognitive status, and c9ALS status. There was a trend for greater TDP-43 pathologic burden in cognitively impaired patients (p = 0.07), though no association with disease duration or progression rate was seen. Shorter disease duration (p = 0.0016), more severe striatal pathology (p = 0.0029), and a trend toward greater whole brain TDP-43 pathology (p = 0.059) were found in c9ALS. Cluster analysis identified "TDP43-limited," "TDP43-moderate," and "TDP43-severe" subgroups. The TDP43-limited group contained more cognitively intact (p = 0.005) and lower extremity onset site (p = 0.019) patients, while other subgroups contained more cognitively impaired patients. We conclude that TDP-43 pathologic burden in ALS is associated with cognitive impairment and c9ALS, but not duration of disease or rate of progression. Further, we demonstrate a subgroup of patients with low TDP-43 burden, lower extremity onset, and intact cognition, which requires further investigation.

Keywords: Amyotrophic lateral sclerosis; Frontotemporal dementia; Motor neuron disease; TDP-43.

© 2017 American Association of Neuropathologists, Inc.

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Figures

FIGURE 1

FIGURE 1

Heat map of TDP-43 inclusion density and extent in 57 ALS patients based on caudal (left) to rostral (right) anatomic regions. This heat map shows the extent and density of TDP-43 neuropathology in 57 ALS patients (study ID labels in rows) by ROIs (columns). The ROIs are organized from more caudal regions at left, progressing rightward through brainstem, subcortical, hippocampal/limbic, and cortical regions. The color bar on the right (values 0–50) represents the density of TDP-43 inclusions in 3 microscopic HPFs (see “Materials and Methods”) with the maximum value at 50 (i.e. ≥50 pathologic inclusions). Gray asterisks indicate missing data points. Data points are sorted from patients with the least (top rows) to most extensive (bottom rows) TDP-43 neuropathology across all ROIs. The patients in the top 3 rows (ALS19, ALS11, and ALS20) had durations of 2533, 2922, and 995 days, respectively. The patients in the bottom 3 rows had durations of 2922, 2112, and 791 days, respectively. All 6 were sALS without c9orf72 expansion.

FIGURE 2

FIGURE 2

Heterogeneity of TDP-43 inclusion pathology in ALS patients. The images emphasize the morphologic and anatomic heterogeneity of TDP-43 pathology in ALS. Several patients had pleomorphic glial inclusions, as shown in inferior olive ((A); note the larger olivary neurons free of inclusion pathology). Other patients had numerous oligodendroglial cytoplasmic inclusions, as shown here in internal capsule (B) and motor cortex ((C); note the larger Betz cell free of inclusion pathology). Patients with c9ALS had more severe striatal TDP-43 pathology and this included several patients with “thread-like” immunoreactive neurites within pencil fibers (D). Pleomorphic neuronal inclusions were also seen in regions not often implicated in ALS. Examples shown here include dense, filamentous inclusions in a neuron of the dentate nucleus (B) and granular inclusions in magnocellular neurons of basal forebrain (F). Five different patients are shown here, including ALS02 (A), ALS57 (B, F), ALS48 (C), ALS52 (D), and ALS36 (E). Images photographed at 600×.

FIGURE 3

FIGURE 3

Canberra distance-based hierarchical clustering based on TDP-43 inclusion data. Graphical demonstration of “TDP43-limited” (Group 1; middle, white border), “TDP43-moderate” (Group 2; right, yellow border), and “TDP43-severe” (Group 3; left, black border) pathologic subgroups as identified by hierarchical clustering using Canberra distance. The heat map reflects the density of TDP-43 inclusion pathology and a color bar is provided at the top right. Patients are represented with columns, and the study ID of each ALS patient is provided (for instance, the right-most listing to the far right is for patient ALS03). Red arrows above the study ID indicate c9ALS patients (n = 15). Rows indicate each of the 34 study ROIs, which are labeled (Table 1). Table 5 shows the analysis of pathologic and clinical variables using the patients identified in these 3 Groups. A Supplementary Data Table S1 is also available that shows an analysis using only the patients in the 6 right-most columns in Group 2 (TDP43-moderate).

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