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. 2013 Jul;74(1):20-38.
doi: 10.1002/ana.23937. Epub 2013 Jun 19.

Stages of pTDP-43 pathology in amyotrophic lateral sclerosis

Johannes Brettschneider #  1   2 , Kelly Del Tredici #  2 , Jon B Toledo  1 , John L Robinson  1 , David J Irwin  1   3 , Murray Grossman  3 , EunRan Suh  1 , Vivianna M Van Deerlin  1   4 , Elisabeth M Wood  1 , Young Baek  1 , Linda Kwong  1   4 , Edward B Lee  1   4 , Lauren Elman  3 , Leo McCluskey  3 , Lubin Fang  2 , Simone Feldengut  2 , Albert C Ludolph  5 , Virginia M-Y Lee  1   4 , Heiko Braak  2 , John Q Trojanowski  1   4
Affiliations

Stages of pTDP-43 pathology in amyotrophic lateral sclerosis

Johannes Brettschneider et al. Ann Neurol. 2013 Jul.

Abstract

Objective: To see whether the distribution patterns of phosphorylated 43kDa TAR DNA-binding protein (pTDP-43) intraneuronal inclusions in amyotrophic lateral sclerosis (ALS) permit recognition of neuropathological stages.

Methods: pTDP-43 immunohistochemistry was performed on 70 μm sections from ALS autopsy cases (N = 76) classified by clinical phenotype and genetic background.

Results: ALS cases with the lowest burden of pTDP-43 pathology were characterized by lesions in the agranular motor cortex, brainstem motor nuclei of cranial nerves V, VII, and X-XII, and spinal cord α-motoneurons (stage 1). Increasing burdens of pathology showed involvement of the prefrontal neocortex (middle frontal gyrus), brainstem reticular formation, precerebellar nuclei, and the red nucleus (stage 2). In stage 3, pTDP-43 pathology involved the prefrontal (gyrus rectus and orbital gyri) and then postcentral neocortex and striatum. Cases with the greatest burden of pTDP-43 lesions showed pTDP-43 inclusions in anteromedial portions of the temporal lobe, including the hippocampus (stage 4). At all stages, these lesions were accompanied by pTDP-43 oligodendroglial aggregates. Ten cases with C9orf72 repeat expansion displayed the same sequential spreading pattern as nonexpansion cases but a greater regional burden of lesions, indicating a more fulminant dissemination of pTDP-43 pathology.

Interpretation: pTDP-43 pathology in ALS possibly disseminates in a sequential pattern that permits recognition of 4 neuropathological stages consistent with the hypothesis that pTDP-43 pathology is propagated along axonal pathways. Moreover, the finding that pTDP-43 pathology develops in the prefrontal cortex as part of an ongoing disease process could account for the development of executive cognitive deficits in ALS.

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Figures

Figure 1
Figure 1. pTDP-43 pathology in the motocortex and spinal cord
a. ALS-associated pTDP-43 pathology was observed in Betz pyramidal cells of layer Vb and in smaller projection neurons of layers II, III, V, and VI in the primary motor area (Brodmann area 4) (case 75, stage 4). b. Layer Vb of the primary motor cortex with affection of Betz pyramidal cells (case 75, stage 4). c. Detail micrograph (framed area in b) shows single Betz cell in higher resolution with pTDP-43 aggregates detectable in the somatodendritic compartment and in unmyelinated initial portions of the axon. d. Pigment-Nissl stain of layer Vb of the motor cortex depicting a Betz pyramidal cell (upper right) and loss of a Betz cell indicated by lipofuscin pigment remnants in the neuropil (pigment incontinence, lower left) (case 14, stage 2). e. Pigment-Nissl stain of spinal cord ventral horn (framed area in f is rotated 90° to the right in e) depicting α-motoneurons alongside neuronal loss indicated by lipofuscin pigment remnants in the neuropil (case 13, stage 2). f. Pigment-Nissl overview of spinal cord ventral and dorsal horns. g,h. Spinal cord α-motoneurons of layer 9 showing pTDP-43 aggregates in neuronal cell bodies as well as in dendrites and axons (heading towards the ventral root) (case 48, stage 3). Note affected oligodendrocytes in h (case 38, stage 3). Scale in a applies to g; scale bar in b is also valid for e; scale bar in d applies to h.
Figure 2
Figure 2. pTDP-43 pathology in bulbar somatomotor nuclei, precerebellar nuclei, and cerebellum
a. Medulla oblongata section showing extensive ALS-associated pTDP-43 aggregates in neurons of both hypoglossal nuclei (XII) as well as within axons of these cells (case 75, stage 4). b. High resolution micrograph of the intramedullary course of fiber tracts generated from motoneurons of the hypoglossal nucleus. The tract itself contains intraaxonal pTDP-43 aggregates; in addition, immunoreactive oligodendrocytes are located in close proximity to the affected axons (case 75, stage 4). c. Cytoplasmic dash-like pTDP-43 aggregates in motoneurons of the hypoglossal nucleus (case 75, stage 4). d. Section through the medulla oblongata at the level of the hypoglossal nucleus shows involvement of precerebellar nuclei characteristic of stage 2 with extensive pTDP-43 pathology in neurons of the inferior olive. Note the predominant involvement of the superior accessory olivary nucleus and upper lamella of the principal olivary nucleus (case 34, stage 3). e. Section of cerebellar cortex demonstrates multiple pTDP-43-immunopositive oligodendrocytes in cerebellar cortical white matter and deep portions of the cerebellar granular layer (case 10, stage 2). Scale bar in a. is also valid for d. Paraffin-embedded 70 μm sections.
Figure 3
Figure 3. pTDP-43 pathology in the striatum, anteromedial fields of the temporal lobe and the hippocampal formation
a. Severe pTDP-43 pathology in striatum involving mainly medium-sized projection neurons (case 69, stage 4). b. Micrograph of a group of medium-sized projection neurons and two large cholinergic local circuit neurons of the striatum showing ALS-associated lesions (case 70, stage 4). c. Immunoreactive medium-sized spiny projection cells of the striatum at higher magnification (case 70, stage 4). d. Mild involvement of hippocampal formation with pTDP-43 pathology in few granular cells of the dentate fascia (case 60, stage 4). e. Marked pTDP-43 pathology in granular cells of the dentate fascia (case 69, stage 4). Uninvolved plexiform layer and portion of the fourth sector of the Ammon’s horn is seen in the right halves of d and e. f. pTDP-43 pathology in pyramidal cells of the entorhinal region, mainly affecting layers pre-β and pri-α. Borders of allocortical entorhinal layers are indicated at the left (diss – lamina dissecans, pre – layers of the external main stratum, pri – layers of the internal main stratum) (case 69, stage 4). g. Transition between entorhinal region (left) and transentorhinal region (right) is indicated by large arrowhead. pTDP-43 pathology in pyramidal cells of the transentorhinal region affects neocortical layers: here, borders of neocortical layers II-V (at right) (case 69, stage 4). Scale bar in a also applies to d and e; scale bar in f is also valid for g. Paraffin-embedded 70 μm sections.
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References

    1. Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. Lancet. 2011 Mar 12;377(9769):942–55. - PubMed
    1. Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006 Oct 6;314(5796):130–3. - PubMed
    1. Lee EB, Lee VM, Trojanowski JQ. Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nature reviews Neuroscience. 2012 Jan;13(1):38–50. - PMC - PubMed

    1. Braak H, Thal DR, Ghebremedhin E, Del Tredici K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. Journal of neuropathology and experimental neurology. 2011 Nov;70(11):960–969. This is the correct reference and not Braak et al. 2006.

    1. Braak H, Del Tredici K. Where, when, and in what form does sporadic Alzheimer’s disease begin? Current opinion in neurology. 2012 Dec;25(6):708–14. - PubMed

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