Acta Neuropathologica

, Volume 127, Issue 3, pp 423–439

Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD)

  • Johannes Brettschneider
  • Kelly Del Tredici
  • David J. Irwin
  • Murray Grossman
  • John L. Robinson
  • Jon B. Toledo
  • Lubin Fang
  • Vivianna M. Van Deerlin
  • Albert C. Ludolph
  • Virginia M.-Y. Lee
  • Heiko Braak
  • John Q. Trojanowski
Original Paper

DOI: 10.1007/s00401-013-1238-y

Cite this article as:
Brettschneider, J., Del Tredici, K., Irwin, D.J. et al. Acta Neuropathol (2014) 127: 423. doi:10.1007/s00401-013-1238-y

Abstract

We examined regional distribution patterns of phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) intraneuronal inclusions in frontotemporal lobar degeneration (FTLD). Immunohistochemistry was performed on 70 μm sections from FTLD-TDP autopsy cases (n = 39) presenting with behavioral variant frontotemporal dementia. Two main types of cortical pTDP-43 pathology emerged, characterized by either predominantly perikaryal pTDP-43 inclusions (cytoplasmic type, cFTLD) or long aggregates in dendrites (neuritic type, nFTLD). Cortical involvement in nFTLD was extensive and frequently reached occipital areas, whereas cases with cFTLD often involved bulbar somatomotor neurons and the spinal cord. We observed four patterns indicative of potentially sequential dissemination of pTDP-43: cases with the lowest burden of pathology (pattern I) were characterized by widespread pTDP-43 lesions in the orbital gyri, gyrus rectus, and amygdala. With increasing burden of pathology (pattern II) pTDP-43 lesions emerged in the middle frontal and anterior cingulate gyrus as well as in anteromedial temporal lobe areas, the superior and medial temporal gyri, striatum, red nucleus, thalamus, and precerebellar nuclei. More advanced cases showed a third pattern (III) with involvement of the motor cortex, bulbar somatomotor neurons, and the spinal cord anterior horn, whereas cases with the highest burden of pathology (pattern IV) were characterized by pTDP-43 lesions in the visual cortex. We interpret the four neuropathological patterns in bvFTD to be consistent with the hypothesis that pTDP-43 pathology can spread sequentially and may propagate along axonal pathways.

Keywords

ALS, amyotrophic lateral sclerosis Frontotemporal lobar degeneration FTLD, frontotemporal dementia FTD Neurodegeneration Proteinopathies TDP-43 

Supplementary material

401_2013_1238_MOESM1_ESM.tif (24.5 mb)
Suppl. Fig. 1. Burden of pTDP-43 pathology in FTLD-TDP with cytoplasmic and neuritic type of cortical pathology. This bar plot illustrates the burden and regional distribution of pTDP-43 pathology in FTLD-TDP with cytoplasmic type of cortical pathology (n = 32) and with neuritic type of cortical pathology (n = 7). Bars indicate median and 95 % confidence interval, significant difference in Wilcoxon Mann–Whitney Test (p < 0.05) is indicated by asterisk. Abbreviations: OG – gyrus rectus and orbital gyri, AMG – amygdala, ENT – entorhinal cortex, HIP – hippocampal formation, MF – middle frontal gyrus, CG – anterior cingulate gyrus, SMT – superior or middle temporal gyrus, STR – striatum, PU – putamen, IO – inferior olive, RN – parvocellular portion of red nucleus, PON – pontine nuclei, TH – thalamus, MOT – agranular motor cortex (Brodmann areas 4 and 6), ANG – angular gyrus, SEN – somatosensory cortex, XII – hypoglossal nucleus, CSC – cervical spinal cord anterior horn, VIS – visual cortex (Brodmann areas 17 and 18), SN – substantia nigra, LC – locus coeruleus, DG – dentate nucleus of cerebellum. (TIFF 25105 kb)
401_2013_1238_MOESM2_ESM.tif (1.1 mb)
Suppl. Fig. 2. pTDP-43 pathology in 70 μm sections of FTLD-TDP with cytoplasmic and neuritic type of cortical pathology in relation to Mackenzie subtypes. This figure illustrates the two main types of cortical pTDP-43 pathology characterized by either predominantly perikaryal pTDP-43 inclusions (cytoplasmic type, cFTLD) or long aggregates in dendrites (neuritic type, nFTLD) and their relation to Mackenzie subtypes of cortical pTDP-43 pathology. The Mackenzie types of cortical pTDP-43 pathology were not readily ascertained in 70 μm sections, and Mackenzie subtypes A and B were combined to cFTLD. a 70 μm section of Mackenzie type A compared to the same tissue block sectioned at 7 μm shown in b, from which upper cortical layers are shown at higher resolution in c. d 70 μm section of Mackenzie type B compared to the same tissue block sectioned at 7 μm shown in e from which upper cortical layers are shown at higher resolution in f. g 70 μm section of Mackenzie type C, as compared to the same tissue block wctioned at 7 μm shown in h, from which upper cortical layers are shown in higher resolution in i. Scale bar in a applies to b, d, e, g, and h. Bar in c is also valid for f and i. (TIFF 1087 kb)
401_2013_1238_MOESM3_ESM.docx (18 kb)
Supplementary material 3 (DOCX 18 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Johannes Brettschneider
    • 1
    • 4
  • Kelly Del Tredici
    • 4
  • David J. Irwin
    • 1
    • 3
  • Murray Grossman
    • 3
  • John L. Robinson
    • 1
  • Jon B. Toledo
    • 1
  • Lubin Fang
    • 4
  • Vivianna M. Van Deerlin
    • 1
    • 2
  • Albert C. Ludolph
    • 5
  • Virginia M.-Y. Lee
    • 1
    • 2
  • Heiko Braak
    • 4
  • John Q. Trojanowski
    • 1
    • 2
  1. 1.Center for Neurodegenerative Disease Research (CNDR)Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of Pathology and Laboratory MedicinePerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  3. 3.Department of NeurologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  4. 4.Clinical Neuroanatomy Section, Department of Neurology, Center for Biomedical ResearchUniversity of UlmUlmGermany
  5. 5.Department of NeurologyUniversity of UlmUlmGermany