Amyotrophic lateral sclerosis and frontotemporal lobar degeneration: a spectrum of TDP-43 proteinopathies

Abstract

It is now established that pathological transactive response DNA-binding protein with a Mr of 43 kD (TDP-43) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis is the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions (now known as FTLD-TDP). In fact, the discovery of pathological TDP-43 solidified the idea that these disorders are multi-system diseases and this led to the concept of a TDP-43 proteinopathy as a spectrum of disorders comprised of different clinical and pathological entities extending from ALS to ALS with cognitive impairment/dementia and FTLD-TDP without or with motor neuron disease (FTLD-MND). These align along a broad disease continuum sharing similar pathogenetic mechanisms linked to pathological TDP-43. We here review salient findings in the development of a concept of TDP-43 proteinopathy as a novel group of neurodegenerative diseases similar in concept to alpha-synucleinopathies and tauopathies.

Fig. 1

Anti-(TAR) DNA binding protein with aMr of 43 (TDP-43) immunohistochemistry in ALS with dementia (A–D,F) and frontotemporal lobar degeneration (FTLD)-TDP (E) (bar = 20 µm). A. Lewy body-like inclusion (large arrow) in the substantia nigra; note the nucleus devoid of the endogenous TDP-43 staining (“cleared nucleus”) (small arrow) that is present in the affected neuron, but not in an unaffected neuron (arrowhead). B. Neuronal cytoplasmic inclusions (large arrow) and neuronal intranuclear inclusion (short arrow) in the visual cortex. C. Fibrillar or skein-like curled inclusions in the sensory cortex (arrow). D. Cleared nuclei coupled with cytoplasmic, granular, or diffuse staining (“pre-inclusions”) (large arrow) in Wernicke’s area. E. Hypothalamus showing dense neuronal cytoplasmic inclusion (large arrow), smaller granular neuronal cytoplasmic TDP-43 immunoreactivity (small arrow), and dystrophic cellular processes (arrowhead). F. Oligodendrocyte with cytoplasmic inclusion in the white matter of cingulate gyrus.

Fig. 2

(TAR) DNA binding protein with a Mr of 43 (TDP-43) multisystem diseases: clinico-pathological spectrum. Schematic illustration of the concept of a clinico-pathological spectrum of the major TPD-43 diseases extending from frontotemporal lobar degeneration (FTLD)-U (ubiquitin-positive) or FTLD-TDP at one end to ALS at the other. Blue arrowhead-like triangles denote clinical syndrome with motor neuron disease decreasing and dementia increasing from left to right. Color change in central box denotes increasing or decreasing spread and severity of TDP-43 pathology in the brain and spinal cord, as an approximate estimation. Specifically, yellow represents predominant involvement of the spinal cord and red represents predominant involvement of cortical areas. Other brain areas are not as explicitly represented in this color-coded diagram. FTLD-U subtype refers to the classification of the cortical pattern of TDP-43 or ubiquitin-positive inclusions according to Sampathu et al. with the addition of an unclassified type denoting the absence of TDP-43 lesions or the presence of a degree of TDP-43 pathology burden that was not sufficient for subtyping. MND = motor neuron disease, ALS-D = ALS with dementia, FTLD-MND = frontotemporal degeneration with MND.