TY - JOUR
T1 - Updated TDP-43 in Alzheimer’s disease staging scheme
AU - Josephs, Keith A.
AU - Murray, Melissa E.
AU - Whitwell, Jennifer L.
AU - Tosakulwong, Nirubol
AU - Weigand, Stephen D.
AU - Petrucelli, Leonard
AU - Liesinger, Amanda M.
AU - Petersen, Ronald C.
AU - Parisi, Joseph E.
AU - Dickson, Dennis W.
N1 - Funding Information:
We wish to thank Kris Johnson, Linda Rousseau, Virginia Phillips and Monica Casey Castanedes for pathological support. The work was supported by grants from the National Institutes of Health [R01 AG037491-06 (KAJ) and P50-AG016574 (RCP)].
Publisher Copyright:
© 2016, Springer-Verlag Berlin Heidelberg.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - In this study, we update the TDP-43 in Alzheimer’s disease staging scheme by assessing the topography of TDP-43 in 193 cases of Alzheimer’s disease, in 14 different brain regions (eight previously described plus six newly reported) and use conditional probability to model the spread of TDP-43 across the 14 brain regions. We show that in addition to the eight original regions we previously reported [amygdala, entorhinal cortex, subiculum, dentate gyrus of the hippocampus, occipitotemporal cortex, inferior temporal cortex, middle frontal cortex and basal ganglia (putamen/globus pallidum)] that TDP-43 is also deposited in the insular cortex, ventral striatum, basal forebrain, substantia nigra, midbrain tectum, and the inferior olive of the medulla oblongata, in Alzheimer’s disease. The conditional probability analysis produced six significantly different stages (P < 0.01), and suggests that TDP-43 deposition begins in the amygdala (stage 1), then moves to entorhinal cortex and subiculum (stage 2); to the dentate gyrus of the hippocampus and occipitotemporal cortex (stage 3); insular cortex, ventral striatum, basal forebrain and inferior temporal cortex (stage 4); substantia nigra, inferior olive and midbrain tectum (stage 5); and finally to basal ganglia and middle frontal cortex (stage 6). This updated staging scheme is superior to our previous staging scheme, classifying 100 % of the cases (versus 94 % in the old scheme), based on criteria provided, and shows clinical significance with some regions and with increasing stage. We discuss the relevance of the updated staging scheme, as well as its impact on the prion-like hypothesis of protein spread in neurodegenerative disease. We also address the issue of whether frontotemporal lobar degeneration with TDP-43 could be the primary pathology in stage 6.
AB - In this study, we update the TDP-43 in Alzheimer’s disease staging scheme by assessing the topography of TDP-43 in 193 cases of Alzheimer’s disease, in 14 different brain regions (eight previously described plus six newly reported) and use conditional probability to model the spread of TDP-43 across the 14 brain regions. We show that in addition to the eight original regions we previously reported [amygdala, entorhinal cortex, subiculum, dentate gyrus of the hippocampus, occipitotemporal cortex, inferior temporal cortex, middle frontal cortex and basal ganglia (putamen/globus pallidum)] that TDP-43 is also deposited in the insular cortex, ventral striatum, basal forebrain, substantia nigra, midbrain tectum, and the inferior olive of the medulla oblongata, in Alzheimer’s disease. The conditional probability analysis produced six significantly different stages (P < 0.01), and suggests that TDP-43 deposition begins in the amygdala (stage 1), then moves to entorhinal cortex and subiculum (stage 2); to the dentate gyrus of the hippocampus and occipitotemporal cortex (stage 3); insular cortex, ventral striatum, basal forebrain and inferior temporal cortex (stage 4); substantia nigra, inferior olive and midbrain tectum (stage 5); and finally to basal ganglia and middle frontal cortex (stage 6). This updated staging scheme is superior to our previous staging scheme, classifying 100 % of the cases (versus 94 % in the old scheme), based on criteria provided, and shows clinical significance with some regions and with increasing stage. We discuss the relevance of the updated staging scheme, as well as its impact on the prion-like hypothesis of protein spread in neurodegenerative disease. We also address the issue of whether frontotemporal lobar degeneration with TDP-43 could be the primary pathology in stage 6.
KW - Alzheimer’s disease
KW - Brainstem
KW - Insular cortex
KW - Limbic
KW - Staging
KW - TDP-43
UR - http://www.scopus.com/inward/record.url?scp=84961140252&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84961140252&partnerID=8YFLogxK
U2 - 10.1007/s00401-016-1537-1
DO - 10.1007/s00401-016-1537-1
M3 - Article
C2 - 26810071
AN - SCOPUS:84961140252
SN - 0001-6322
VL - 131
SP - 571
EP - 585
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 4
ER -