Neuron loss and degeneration in the progression of TDP-43 in frontotemporal lobar degeneration

Ahmed Yousef,Linda K Kwong,David J Irwin,Yan Xu,Edward B Lee,Eunran Suh,Lior Rennert,Virginia M.-Y Lee,Sharon X Xie,John L Robinson,John Q Trojanowski,Matthew D Byrne,Vivianna M Van Deerlin,Murray Grossman

doi:10.1186/s40478-017-0471-3

Ahmed Yousef, Linda K Kwong + Show 12 more

Open Access

https://doi.org/10.1186/s40478-017-0471-3

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Abstract

Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is associated with the accumulation of pathological neuronal and glial intracytoplasmic inclusions as well as accompanying neuron loss. We explored if cortical neurons detected by NeuN decreased with increasing TDP-43 inclusion pathology in the postmortem brains of 63 patients with sporadic and familial FTLD-TDP. Semi-automated quantitative algorithms to quantify histology in tissue sections stained with antibodies specific for pathological or phosphorylated TDP-43 (pTDP-43) and NeuN were developed and validated in affected (cerebral cortex) and minimally affected (cerebellar cortex) brain regions of FTLD-TDP cases. Immunohistochemistry (IHC) for NeuN and other neuronal markers found numerous neurons lacking reactivity, suggesting NeuN may reflect neuron health rather than neuron loss in FTLD. We found three patterns of NeuN and pTDP-43 reactivity in our sample of cortical tissue representing three intracortical region-specific stages of FTLD-TDP progression: Group 1 showed low levels of pathological pTDP-43 and high levels NeuN, while Group 2 showed increased levels of pTDP-43, and Group 3 tissues were characterized by reduced staining for both pTDP-43 and NeuN. Comparison of non-C9orf72/GRN FTLD-TDP with cases linked to both GRN mutations and C9orf72 expansions showed a significantly increased frequency of Group 3 histopathology in the latter cases, suggesting more advanced cortical disease. Hence, we propose that IHC profiles of pTDP-43 and NeuN reflect the burden of pTDP-43 and its deleterious effects on neuron health.

Highlights

Frontotemporal lobar degeneration (FTLD) is the second most common cause of neurodegenerative dementia in patients younger than 65 [21, 50]
Semi-automated quantitative algorithm development Tissue sections from our cohort were stained for NeuN and phosphorylated TDP-43 (pTDP-43) inclusions to develop the counting algorithms used in this study, and they serve as a relative index of NeuN level and TDP-43 pathology (Fig. 1a)
The majority of the measurements were within limits of agreement and the bias was quite small (NeuN = −0.019; pTDP-43 inclusions = 0.055)

Summary

Introduction

Frontotemporal lobar degeneration (FTLD) is the second most common cause of neurodegenerative dementia in patients younger than 65 [21, 50]. About 40% of FTLD patients have a family history of a neurodegenerative disease, and the most common genetic causes of FTLD include C9orf expansions and mutations in the granulin. FTLD-TDP is a disorder characterized by diverse clinical, genetic, and pathological features [18, 42]. Macroscopic examination of the postmortem brains of patients diagnosed with clinical frontotemporal degeneration (FTD) generally reveals marked atrophy and neuronal loss, Yousef et al Acta Neuropathologica Communications (2017) 5:68 especially in the temporal and frontal lobes at end stage disease. FTLD can present with overlapping clinical amyotrophic lateral sclerosis (ALS), a motor neuron disease typically marked by underlying TDP-43 pathology [9, 18]. The C9orf mutation is the most common cause of familial FTD, FTDALS, and ALS [40]

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