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. 2022 Dec;28(12):2547-2554.
doi: 10.1038/s41591-022-02075-9. Epub 2022 Nov 24.

CSF tau microtubule-binding region identifies pathological changes in primary tauopathies

Kanta Horie  1   2 , Nicolas R Barthélemy  1   2 , Salvatore Spina  3 , Lawren VandeVrede  3 , Yingxin He  1   2 , Ross W Paterson  4 , Brenton A Wright  5 , Gregory S Day  6 , Albert A Davis  1   7 , Celeste M Karch  7   8   9 , William W Seeley  3 , Richard J Perrin  1   7   9   10 , Rama K Koppisetti  1   8 , Faris Shaikh  1 , Argentina Lario Lago  3 , Hilary W Heuer  3 , Nupur Ghoshal  1   8 , Audrey Gabelle  11 , Bruce L Miller  3 , Adam L Boxer  3 , Randall J Bateman  12   13   14   15 , Chihiro Sato  16   17
Affiliations

CSF tau microtubule-binding region identifies pathological changes in primary tauopathies

Kanta Horie et al. Nat Med. 2022 Dec.

Abstract

Despite recent advances in fluid biomarker research in Alzheimer's disease (AD), there are no fluid biomarkers or imaging tracers with utility for diagnosis and/or theragnosis available for other tauopathies. Using immunoprecipitation and mass spectrometry, we show that 4 repeat (4R) isoform-specific tau species from microtubule-binding region (MTBR-tau275 and MTBR-tau282) increase in the brains of corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD)-MAPT and AD but decrease inversely in the cerebrospinal fluid (CSF) of CBD, FTLD-MAPT and AD compared to control and other FTLD-tau (for example, Pick's disease). CSF MTBR-tau measures are reproducible in repeated lumbar punctures and can be used to distinguish CBD from control (receiver operating characteristic area under the curve (AUC) = 0.889) and other FTLD-tau, such as PSP (AUC = 0.886). CSF MTBR-tau275 and MTBR-tau282 may represent the first affirmative biomarkers to aid in the diagnosis of primary tauopathies and facilitate clinical trial designs.

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Conflict of interest statement

K.H. is an Eisai-sponsored voluntary research associate professor at Washington University and has received salary from Eisai. Washington University and R.J.B. have equity ownership interest in C2N Diagnostics and R.J.B. receives income from C2N Diagnostics for serving on the scientific advisory board. R.J.B., N.R.B., K.H. and C.S. may receive income based on technology (Methods to detect MTBR tau isoforms and use thereof) licensed by Washington University to C2N Diagnostics. R.J.B. has received research funding from Avid Radiopharmaceuticals, Janssen, Roche/Genentech, Eli Lilly, Eisai, Biogen, AbbVie, Bristol Myers Squibb and Novartis. RJB serves on the Roche Gantenerumab Steering Committee as an unpaid member. S.S. has received consultation fees from Techspert.io, Acsel Health and PRECISIONxtract. L.V. has served as a consultant for Retrotope. R.W.P. has received honoraria as an educational speaker for GE Healthcare. B.A.W. has participated or is currently participating in clinical research sponsored by Acadia, Biogen, Global Kinetics, Neurocrine, Prilenia, PTC, Roche, Sage, Vaccinex, Transposon and Triplet Therapeutics. G.S.D.’s research is supported by the NIH (K23AG064029, U01AG057195, U19AG032438), the Alzheimer’s Association and Chan Zuckerberg Initiative. He serves as a consultant for Parabon NanoLabs, as a topic editor (dementia) for DynaMed (EBSCO) and as the Clinical Director of the Anti-NMDA Receptor Encephalitis Foundation (Canada; uncompensated). He is the co-project principal investigator for a clinical trial in anti-N-methyl-D-aspartate receptor encephalitis, which receives support from Horizon Pharmaceuticals. He has developed educational materials for PeerView Media and Continuing Education. His institution has received support from Eli Lilly for the development and presentation of educational content at an academic conference. He owns stock in ANI Pharmaceuticals. A.A.D. received compensation for performing procedures related to a clinical trial sponsored by Roche and received honoraria as a speaker from the Glaucoma Research and BrightFocus Foundations. W.W.S. received consulting fees from Guidepoint Global, GLG Council and BridgeBio. N.G. has participated or is currently participating in clinical trials of anti-dementia drugs sponsored by the following companies: Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen Immunotherapy, Novartis, Pfizer, Wyeth and Roche. B.L.M. receives royalties from Cambridge University Press, Johns Hopkins University Press, Taylor & Francis Group, Guilford Publications, Oxford University Press and Elsevier, and honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, such as UCLA Grand Rounds, UCI MIND seminar series, Taipei Medical University, Dementia Center and Korean Dementia Society talks. A.L.B. has served as a consultant for Alector Therapeutics, Arkuda, Arvinas, AZTherapeutics, Boehringer Ingelheim, Denali, GSK, Humana, Oligomerix, Oscotec, Roche, Third Rock, Transposon Therapeutics, TrueBinding and Wave. Y.H., C.M.K., R.J.P., R.K.K., F.S., A.L.L., H.W.H. and A.G. declare no competing interests.

Figures

Fig. 1
Fig. 1. 4R-specific insoluble brain MTBR-tau is enriched in CBD, FTLD-MAPT, AD and PSP.
a, Schematic of the quantified peptides of t-tau181–190 and 4R isoform-specific MTBR-tau in the R2 region (gray bars, MTBR-tau275 and MTBR-tau282). The relative abundance of each MTBR-tau was normalized to the t-tau peptide. b,c, MTBR-tau275/t-tau (b) and MTBR-tau282/t-tau (c) were measured in the tauopathy patient’s insoluble brain fractions from the SFG (circle, n = 54) and insula (triangle, n = 8). Both MTBR-tau species were most enriched in CBD (n = 12) and FTLD-MAPT (n = 8). PSP (n = 16) and AD (n = 7) had moderate enrichment. AGD (n = 1), PiD (n = 3) and FTLD-TDP (n = 12) did not change in MTBR-tau275 or MTBR-tau282 compared to normal control (n = 3). The red (n = 9) and blue (n = 1) filled circles indicate AD and PSP copathology, respectively. *P < 0.05, **P < 0.01, ****P < 0.0001. The box plots show the minimum, 25th percentile, median, 75th percentile and maximum. Differences in biomarker values were assessed with a one-way ANOVA. A two-sided P < 0.05 was considered statistically significant and corrected for multiple comparisons using a Benjamini–Hochberg FDR set at 5%.
Fig. 2
Fig. 2. 4R-specific CSF MTBR-tau decreases in CBD, FTLD-MAPT and AD.
a, Schematic of the quantified peptides of t-tau 212–221, truncation and 4R isoform-specific MTBR-tau in the R2 region (gray bars, MTBR-tau275 and MTBR-tau282). The relative abundance of each MTBR-tau was normalized to the t-tau peptide. b,c, CSF MTBR-tau275/t-tau (b) and MTBR-tau282/t-tau (c) significantly decreased in CBD (n = 18), AD (n = 10) and FTLD-MAPT (n = 5) compared to normal control (n = 29), FTLD-TDP (n = 21) and other FTLD-tau. FTLD-MAPT P301L (red, n = 2), R406W (blue, n = 2) and S305I (green, n = 1) decreased in MTBR-tau/t-tau measurements in this order. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. The box plots show the minimum, 25th percentile, median, 75th percentile and maximum. Differences in biomarker values were assessed with a one-way ANOVA. A two-sided P < 0.05 was considered statistically significant and corrected for multiple comparisons using a Benjamini–Hochberg FDR set at 5%.
Fig. 3
Fig. 3. CSF soluble MTBR-tau correlates with brain insoluble MTBR-tau aggregates.
a,b, MTBR-tau275/t-tau (a) and MTBR-tau282/t-tau (b) from paired CSF and brain inversely correlated in tauopathies, FTLD-TDP and control (n = 54, r = −0.27, P = 0.049, −0.45, P = 0.0006, respectively). c,d, MTBR-tau275/t-tau (c) and MTBR-tau282/t-tau (d) from paired CSF and brain had higher correlations (r = −0.61, P = 0.0004 and r = −0.75, P < 0.0001, respectively) in 4R tauopathies (CBD, PSP and AGD, n = 29). e,f, MTBR-tau275/t-tau (e) and MTBR-tau282/t-tau (f) from paired CSF and brain correlated in CBD (n = 12, r = −0.25, P = 0.43 and r = −0.31, P = 0.33, respectively). The gray shadow represents the 95% confidence intervals for the linear regression.
Extended Data Fig. 1
Extended Data Fig. 1. 4R CSF MTBR-tau assay is reproducible and stable in repeated lumbar punctures.
CSF MTBR-tau275/t-tau was measured in 25 participants (#01-#25) who had 3 to 5 repeated lumbar punctures within 4 months. FTLD-MAPT P301L (red, n = 2, #02, 03), symptomatic FTLD-MAPT R406W (blue, n = 1, #05), and pathologically-confirmed CBD (green, n = 2, #10 and #11) had decreased CSF MTBR-tau275/t-tau. Data are presented as mean values + /− SD. CBS: corticobasal syndrome, PSP-RS: progressive supranuclear palsy-Richardson’s syndrome, FTLD-MAPT: frontotemporal lobar degeneration with MAPT mutations.
Extended Data Fig. 2
Extended Data Fig. 2. CSF MTBR-tau275/t-tau decreases in clinically diagnosed CBS-PSP continuum and FTLD-MAPT.
CSF MTBR-tau275/t-tau decreased in clinically diagnosed CBS-PSP continuum (n = 7), and genetically confirmed FTLD-MAPT (red: n = 3, P301L, blue: n = 5, R406W) compared to NC (n = 88). Differences in biomarker values were assessed with one-way ANOVAs. A two-sided p < 0.05 was considered statistically significant and corrected for multiple comparisons using Benjamini-Hochberg false discovery rate (FDR) method with FDR set at 5%. *P < 0.05. The box plots show the minimum, 25 percentile, median, 75 percentile, and maximum. NC: normal control, bvFTD: behavioral variant frontotemporal dementia (n = 28), PSP-RS: progressive supranuclear palsy-Richardson’s syndrome (n = 16), CBS: corticobasal syndrome (n = 15), AD: Alzheimer’s disease (n = 80), FTLD-MAPT: frontotemporal lobar degeneration with MAPT mutations (n = 8).
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