TY - JOUR
T1 - Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD)
AU - Brettschneider, Johannes
AU - Del Tredici, Kelly
AU - Irwin, David J.
AU - Grossman, Murray
AU - Robinson, John L.
AU - Toledo, Jon B.
AU - Fang, Lubin
AU - Van Deerlin, Vivianna M.
AU - Ludolph, Albert C.
AU - Lee, Virginia M.Y.
AU - Braak, Heiko
AU - Trojanowski, John Q.
N1 - Funding Information:
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.
PY - 2014/3
Y1 - 2014/3
N2 - 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.
AB - 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.
KW - ALS, amyotrophic lateral sclerosis
KW - Frontotemporal lobar degeneration
KW - FTD
KW - FTLD, frontotemporal dementia
KW - Neurodegeneration
KW - Proteinopathies
KW - TDP-43
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UR - http://www.scopus.com/inward/citedby.url?scp=84896726031&partnerID=8YFLogxK
U2 - 10.1007/s00401-013-1238-y
DO - 10.1007/s00401-013-1238-y
M3 - Article
C2 - 24407427
AN - SCOPUS:84896726031
SN - 0001-6322
VL - 127
SP - 423
EP - 439
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 3
ER -