The pathological sequestration of TAR DNA-binding protein 43 (TDP-43, encoded by TARDBP) into cytoplasmic pathological inclusions characterizes the distinct clinical syndromes of amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia, while also co-occurring in a proportion of patients with Alzheimer's disease, suggesting that the regional concentration of TDP-43 pathology has most relevance to specific clinical phenotypes. This has been reflected in the three different pathological staging schemes for TDP-43 pathology in these different clinical syndromes, with none of these staging schemes including a preclinical phase similar to that which has proven beneficial in other neurodegenerative diseases. To apply each of these three staging schemes for TDP-43 pathology, the clinical phenotype must be known undermining the potential predictive value of the pathological examination. The present study set out to test whether a more unified approach could accurately predict clinical phenotypes based solely on the regional presence and severity of TDP-43 pathology. The selection of brain regions of interest was based on key regions routinely sampled for neuropathological assessment under current consensus criteria that have also been used in the three TDP-43 staging schemes. The severity of TDP-43 pathology in these regions of interest was assessed in four clinicopathological phenotypes: amyotrophic lateral sclerosis (n = 27, 47-78 years, 15 males), behavioural variant frontotemporal dementia (n = 15, 49-82 years, seven males), Alzheimer's disease (n = 26, 51-90 years, 11 males) and cognitively normal elderly individuals (n = 17, 80-103 years, nine males). Our results demonstrate that the presence of TDP-43 in the hypoglossal nucleus discriminates patients with amyotrophic lateral sclerosis with an accuracy of 98%. The severity of TDP-43 deposited in the anterior cingulate cortex identifies patients with behavioural variant frontotemporal dementia with an accuracy of 99%. This identification of regional pathology associated with distinct clinical phenotypes suggests key regions on which probabilistic pathological criteria, similar to those currently available for Alzheimer's disease and dementia with Lewy bodies, can be developed for TDP-43 proteinopathies. We propose and validate a simplified probabilistic statement that involves grading the presence of TDP-43 in the hypoglossal nucleus and the severity of TDP-43 in the anterior cingulate for the pathological identification of TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.