TDP-43 Vasculopathy in the Spinal Cord in Sporadic Amyotrophic Lateral Sclerosis (sALS) and Frontal Cortex in sALS/FTLD-TDP.

Isidro Ferrer,Margarita Carmona,Pol Andrés-Benito,Abdelilah Assialioui,Mónica Povedano

doi:10.1093/jnen/nlaa162

Abstract

Sporadic amyotrophic lateral sclerosis (sALS) and FTLD-TDP are neurodegenerative diseases within the spectrum of TDP-43 proteinopathies. Since abnormal blood vessels and altered blood-brain barrier have been described in sALS, we wanted to know whether TDP-43 pathology also occurs in blood vessels in sALS/FTLD-TDP. TDP-43 deposits were identified in association with small blood vessels of the spinal cord in 7 of 14 cases of sALS and in small blood vessels of frontal cortex area 8 in 6 of 11 FTLD-TDP and sALS cases, one of them carrying a GRN mutation. This was achieved using single and double-labeling immunohistochemistry, and double-labeling immunofluorescence and confocal microscopy. In the sALS spinal cord, P-TDP43 Ser403-404 deposits were elongated and parallel to the lumen, whereas others were granular, seldom forming clusters. In the frontal cortex, the inclusions were granular, or elongated and parallel to the lumen, or forming small globules within or in the external surface of the blood vessel wall. Other deposits were localized in the perivascular space. The present findings are in line with previous observations of TDP-43 vasculopathy in a subset of FTLD-TDP cases and identify this pathology in the spinal cord and frontal cortex in a subset of cases within the sALS/FTLD-TDP spectrum.

Highlights

Sporadic amyotrophic lateral sclerosis and most cases of frontotemporal lobar degeneration with ubiquitinpositive inclusions (FTLD-U) are considered to be within the same spectrum [1]
TDP-43 was expressed in the nucleus of cells of the blood vessel walls including capillaries of the gray and white matter, and meninges
Reduced TDP-43 immunoreactivity was observed in a few vascular nuclei in the anterior horn and the white matter tracts in Sporadic amyotrophic lateral sclerosis (sALS); this reduction was selective, as TDP-43 immunoreactivity was preserved in other cells located in the vicinity (Fig. 1E)

Summary

Introduction

Sporadic amyotrophic lateral sclerosis (sALS) and most cases of frontotemporal lobar degeneration with ubiquitinpositive inclusions (FTLD-U) are considered to be within the same spectrum [1]. This is supported by the identification of trans-activation response element (TAR) DNA binding protein-43 (TDP-43), encoded by TARDBP gene, as the major pathological protein in the inclusions of FTLD-U (hereinafter FTLD-TDP) with or without motor neuron disease, and in sALS [2]. In FTLD-TDP, TDP-43-immunoreactive aggregates are neuronal cytoplasmic inclusions (NCIs), thin and thick dystrophic neurites (DNs), and neuronal intranuclear inclusions (NIIs), in addition to GCIs [3].

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