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Title: Hippocampal sclerosis in Lewy body disease is a TDP-43 proteinopathy similar to FTLDTDP Type A
Authors and Affiliations
Naoya Aoki, MD1, Melissa E. Murray, PhD1, Kotaro Ogaki, MD, PhD1, Shinsuke Fujioka, MD1,2,
Nicola J. Rutherford1,3, Rosa Rademakers, PhD1, Owen A. Ross, PhD1, and Dennis W.
Dickson, MD1
1
Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224
2
Department of Neurology, Fukuoka University, Fukuoka, Japan
3
Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease,
McKnight Brain Institute, University of Florida, 1275 Center Drive, Gainesville, FL 32610-0244
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Supplemental Material
Supplemental Methods
To identify a validation cohort, we used the same exclusion criteria
as stated for the LBD cohort in the Case Material section. Additionally, we excluded for LBD,
HpScl, and severe Alzheimer’s disease pathology by limiting our cohort to Braak NFT stage ≤III
(n=132). A section of the hippocampus was screened with TDP-43 immunohistochemistry
(MC2085) in all cases. TDP-43 subtype and severity of CA1 fine neurites were assessed on
sections that were immunostained with phosphorylated TDP-43 antibody (pS409/410) as stated
for the LBD cohort in the Case Material section.
Supplemental Figure legend
Histologic features of “pre-HpScl” in a patient from the non-
LBD cohort. The hippocampus has no neuronal loss in the CA1 sector (a), but abundant TDP43-positive fine neurites (b). Neuronal cytoplasmic inclusions (NCIs) in the dentate fascia (c).
Mixture of NCIs and dystrophic neurites in the occipitotemporal gyrus (d). H&E staining (a).
TDP-43 pS409/410 (b-d). Scale bars: a-d; 50um.
Rev1; Resp3
Supplemental Table 1 legend
All data are displayed as median (25th, 75th range), unless
otherwise noted. TMEM106B rs1990622 C allele, GRN rs5848 T allele, and APOE ε4 allele
carriers are displayed as number genotyped out of available cases.
Supplemental Table 2 legend
otherwise noted.
All data is displayed as median (25th, 75th range), unless
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Supplemental Table 1.
Rev1; Resp3
Demographics, pathology and genetics of case material excluding overlap cases with Murray et
al. 2014 [21]
HpScl
n=14
Not HpScl
n=407
P-value
9 (64%)
286 (70%)
0.854
83 (78, 87)
78 (72, 83)
0.007
1050 (965, 1163)
1195 (1080, 1295)
0.003
III (II, VI)
III (II, IV)
0.108
5 (2, 5)
3 (2, 5)
0.063
Diffuse
8 (57%)
232 (57%)
0.792
Limbic
6 (43%)
175 (43%)
14 (100%)
59 (14%)
<0.001
14/14 (100%)
29/59 (50%)
0.002
Type B/NFT
0/14 (0%)
15/59 (25%)
Unclassified
0/14 (0%)
15/59 (25%)
TMEM106B, C allele carriers#
7/14 (50%)
213/316 (67%)
0.288
GRN, T allele carriers
8/14 (57%)
161/316 (51%)
0.857
APOE, ε4 allele carriers
10/14 (71%)
147/323 (46%)
0.103
Demographic characteristics
Male
Age at death, years
Post-mortem findings
Brain weight, grams
Braak NFT stage
Thal amyloid-β phase
Lewy body subtype
TDP-43 positivity
Type A
Genetic findings
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Supplemental Table 2.
Comparison between non-LBD and LBD cohorts without HpScl or severe AD pathology
Non-LBD without HpScl
(Braak NFT stage 0-III)
LBD without HpScl
(Braak NFT stage 0-III)
n=132
n=297
82 (76, 87)
77 (72, 82)
<0.001
Braak NFT stage
II (II, III)
III (II, III)
0.064
Thal amyloid-β phase
2 (0, 3)
2.5 (2, 3)
<0.001
6 (4.5%)
27 (9%)
0.151
Type A
3/6 (50%)
12/27 (44%)
0.970
Type B/NFT
1/6 (17%)
5/27 (19%)
Unclassified
2/6 (33%)
10/27 (37%)
1 (0.76%)
8 (2.7%)
Age at death, years
TDP-43 positivity
Pre-HpScl
P-value
0.354