MAPT subhaplotypes in corticobasal degeneration: assessing associations with disease risk, severity of tau pathology, an
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MAPT subhaplotypes in corticobasal degeneration: assessing associations with disease risk, severity of tau pathology, and clinical features Rebecca R. Valentino1†, Shunsuke Koga1†, Ronald L. Walton1, Alexandra I. Soto‑Beasley1, Naomi Kouri1, Michael A. DeTure1, Melissa E. Murray1, Patrick W. Johnson2, Ronald C. Petersen3, Bradley F. Boeve3, Ryan J. Uitti4, Zbigniew K. Wszolek4, Dennis W. Dickson1*, Owen A. Ross1,5 and Michael G. Heckman2*
Abstract The microtubule-associated protein tau (MAPT) H1 haplotype is the strongest genetic risk factor for corticobasal degeneration (CBD). However, the specific H1 subhaplotype association is not well defined, and it is not clear whether any MAPT haplotypes influence severity of tau pathology or clinical presentation in CBD. Therefore, in the current study we examined 230 neuropathologically confirmed CBD cases and 1312 controls in order to assess associations of MAPT haplotypes with risk of CBD, severity of tau pathology (measured as semi-quantitative scores for coiled bodies, neurofibrillary tangles, astrocytic plaques, and neuropil threads), age of CBD onset, and disease duration. After cor‑ recting for multiple testing (P 0.01 after Bonferroni correction), and genotype call rates were 100% for each variant. Genotype frequencies for each variant are summarized in Additional file 1: Table S1. Neuropathological assessment
For a subset of 196 CBD cases, a single neuropathologist (DWD) assessed semi-quantitative tau pathology measures on a 0–3 severity scale (0 = none; 1 = mild; 2 = moderate; 3 = severe). All sections were processed identically with phospho-tau monoclonal antibody (CP13, from Dr. Peter Davies, Feinstein Institute, Long Island, NY). Immunochemistry was performed using a DAKO Autostainer. CB, NFT, AP, and NT were evaluated and scored in 21 different neuroanatomical regions which are vulnerable to CBD pathology (Additional file 1: Table S2) [8]. For each of the four different tau pathology measures
Valentino et al. acta neuropathol commun
(2020) 8:218
Page 3 of 9
Table 1 Characteristics of CBD patients and controls Variable Age (years)1
CBD patients (N = 230) 70 (46, 96)
Controls (N = 1312) 69 (45, 92)
Sex Female
119 (51.7%)
611 (46.6%)
Male
111 (48.3%)
701 (53.4%)
Age of CBD onset (years)
64 (41, 86)
N/A
Disease duration (years)
6 (2, 16)
N/A
0
27 (13.8%)
N/A
I
36 (18.4%)
N/A
II
66 (33.7%)
N/A
III
53 (27.0%)
N/A
IV
11 (5.6%)
N/A
V
2 (1.0%)
N/A
VI
1 (0.5%)
N/A
Braak stage
Thal phase 0
105 (53.6%)
N/A
1
35 (17.9%)
N/A
2
24 (12.2%)
N/A
3
25 (12.8%)
N/A
4
3 (1.5%)
N/A
5 CB overall tau pathology score
4 (2.0%) 0.77 (0.23, 1.75)
N/A N/A
NFT overall tau pathology score
2.19 (1.13, 2.62)
N/A
AP overall tau pathology score
0.53 (0.24, 1.04)
N/A
NT overall tau pathology score
2.52 (1.24, 2.95)
N/A
CBD corticobasal degeneration, CB coiled bodies, NFT neurofibrillary tangles, AP astrocytic plaques, NT neuropil threads The sample median (minimum, maximum) is given f
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