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.
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Acknowledgments
We thank the many patients who contributed to this study. We are also grateful to Kevin Raible, Terry Schuck, Sigrid Baumann, Gabriele Ehmke, Simone Feldengut, Julia Straub, and Thi Phuong Thu Brettschneider for technical support, together with David Ewert (University of Ulm) for assistance with the graphics. This study was supported by the NIH (AG033101, AG017586, AG010124, AG032953, AG039510, NS044266), the Wyncote Foundation, and the Koller Family Foundation. VM-YL is the John H. Ware, 3rd, Professor of Alzheimer’s Disease Research. JQT is the William Maul Measey-Truman G. Schnabel, Jr. Professor of Geriatric Medicine and Gerontology. DJI is supported by T32-AG000255. This study was supported by the German BMBF FTLD Consortium.
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J. Brettschneider, K. Del Tredici, D. J. Irwin contributed equally.
H. Braak, J. Q. Trojanowski are Senior authors.
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401_2013_1238_MOESM1_ESM.tif
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
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)
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Brettschneider, J., Del Tredici, K., Irwin, D.J. et al. Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD). Acta Neuropathol 127, 423–439 (2014). https://doi.org/10.1007/s00401-013-1238-y
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DOI: https://doi.org/10.1007/s00401-013-1238-y