Abstract
IntroductionThe progression of amyotrophic lateral sclerosis (ALS) through the brain has recently been staged using independent neuropathological and neuroimaging modalities. The two schemes tie into the concept of pathological spread through corticofugal axonal transmission that stems from observation of oligodendrocyte pTDP-43 aggregates along with neuronal inclusions. Here, we aimed to assess evidence of transmission along axonal pathways by looking for pTDP-43 oligodendrocyte pathology in involved white matter tracts, and to present a first validation of the neuropathological staging scheme.pTDP-43 immunohistochemistry was performed in select white matter tracts and grey matter regions from the staging scheme in postmortem-confirmed ALS cases (N = 34). Double-labelling immunofluorescence was performed to confirm co-localisation of pTDP-43 immunoreactivity to oligodendrocytes.ResultsWhile pTDP-43 immunoreactive oligodendrocytes were frequent in the white matter under the motor and sensory cortices, similar assessment of the white matter along the corticospinal tract and in the corpus callosum and cingulum bundle of the same cases revealed no pTDP-43 pathology, questioning the involvement of oligodendrocytes in pathological propagation. The assessment of Betz cell loss revealed that the lack of deep white matter pTDP-43 oligodendrocyte pathology was not due to an absence of motor axons. Assessment of the propagation of pathology to different grey matter regions validated that all cases could be allocated to one of four neuropathological stages, although Stage 4 cases were found to differ significantly in age of onset (~10 years older) and disease duration (shorter duration than Stage 3 and similar to Stage 2).ConclusionsFour stages of ALS neuropathology can be consistently identified, although evidence of sequential clinical progression requires further assessment. As limited pTDP-43 oligodendrocyte pathology in deep corticospinal and other white matter tracts from the motor cortex was observed, the propagation of pathology between neurons may not involve oligodendrocytes and the interpretation of the changes observed on neuroimaging should be modified accordingly.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0226-y) contains supplementary material, which is available to authorized users.
Highlights
The progression of amyotrophic lateral sclerosis (ALS) through the brain has recently been staged using independent neuropathological and neuroimaging modalities
While Phosphorylated 43-kDA TAR DNA-binding protein (pTDP-43) immunoreactive oligodendrocytes were frequent in the white matter under the motor and sensory cortices, similar assessment of the white matter along the corticospinal tract and in the corpus callosum and cingulum bundle of the same cases revealed no pTDP-43 pathology, questioning the involvement of oligodendrocytes in pathological propagation
The assessment of Betz cell loss revealed that the lack of deep white matter pTDP-43 oligodendrocyte pathology was not due to an absence of motor axons
Summary
The progression of amyotrophic lateral sclerosis (ALS) through the brain has recently been staged using independent neuropathological and neuroimaging modalities. We aimed to assess evidence of transmission along axonal pathways by looking for pTDP-43 oligodendrocyte pathology in involved white matter tracts, and to present a first validation of the neuropathological staging scheme. PTDP-43 immunohistochemistry was performed in select white matter tracts and grey matter regions from the staging scheme in postmortem-confirmed ALS cases (N = 34). Amyotrophic lateral sclerosis (ALS) with both upper and lower motor neuron involvement is the most common presentation, accounting for more than 75 % of cases with motor neuron disease [1, 2]. Brettschneider and colleagues defined four neuropathological stages of ALS [6], proposing that lesions first develop in the motor cortex, brainstem motor nuclei of cranial nerves V, VII and X-XII, and spinal cord α-motoneurons in Stage 1. The earliest and most common lesions are found in oligodendrocytes [6], and in association with animal studies, it has been proposed that early oligodendrocyte involvement is important for the propagation of pathology to neurons in ALS [7, 11,12,13,14]
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