Clinical Significance of TDP-43 Neuropathology in Amyotrophic Lateral Sclerosis

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.

White matter changes in the perforant path area in patients with amyotrophic lateral sclerosis

“…Furthermore, the fact that most ALS cases were diagnosed with stage 1 at time of death ( Table 1), suggests that pTDP-43 proteinopathy is not necessarily a marker for the symptomatic severity of ALS. This largely agrees with studies showing no correlation between disease duration/progression and pTDP-43 burden [13].…”

“…Less is known about the involvement of the Papez circuitry in patients with ALS. Previous studies have demonstrated a relationship between pTDP-43 pathology in ALS patients and their cognitive decline [6,13], suggesting a relation to limbic system impairment. Furthermore, an accumulating body of evidence supports involvement of the perforant pathway, the tract connecting the entorhinal cortex with the hippocampal formation as part of the Papez circuit, in late stages of ALS [14,15].…”

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

“…After PBS washes, sections were incubated in appropriate secondary antibodies in blocking solution: Alexa Fluor 488 (1:1000, Thermo Fisher Scientific, Rockford, IL, USA), Alexa Fluor 647 (1:1000, Thermo Fisher Scientific, Rockford, IL, USA) and Cy3-conjugated (1:1000, Molecular Probes, Eugene, OR, USA) for 2 h at room temperature (RT). Antigen retrieval with 0.01 M sodium citrate, pH 9, for 3 h in a water bath at 80 °C was performed prior to blocking for rabbit anti-RanGap1 antibody (1:250; Abcam, Cambridge, MA, USA) as previously described [14]. Sections were counterstained with DAPI (1:5000).…”

Rapidly progressive amyotrophic lateral sclerosis is associated with microglial reactivity and small heat shock protein expression in reactive astrocytes

“…As SDD is associated with relative preservation of neurons and only moderate levels of pTDP‐43 inclusions, spinal cord neuronal pathology itself does not explain the rapid clinical decline of these patients. In ALS brain, the density of TDP‐43 inclusions does not correlate with disease duration or with rate of progression . Rather, glial responses to motor neuron degeneration may determine disease severity.…”