New Data Bolsters MTBR-Tau243 as Fluid Marker for Tangles

Series - Clinical Trials on Alzheimer's Disease (CTAD) 2022:

Much of the focus on blood biomarkers for Alzheimer’s disease has recently been on tracking amyloid plaques using phospho-tau217 and the Aβ42/40 ratio (see Part 9 and Part 14 of this series). However, a different snippet of tau has caught researchers’ attention for its ability to flag the presence of neurofibrillary tangles and cognitive decline. It is MTBR-tau243, which spans residues 243 to 254 within tau’s microtubule-binding region.

  • MTBR-tau243 ticks up in the CSF when neurofibrillary tangles form.
  • This fragment also correlates with waning cognition.
  • It tracked with MMSE scores almost as well as tau PET.

At the Clinical Trials on Alzheimer’s Disease conference, held November 29 through December 2 in San Francisco, Kanta Horie of Washington University in St. Louis reported that cerebrospinal fluid levels of MTBR-tau243 closely tracked with tau PET, distinguishing amyloid-positive people with tangles from amyloid-positive people without tangles. The tau fragment also correlated with Mini-Mental State Exam scores, meaning it might help stage AD without an expensive PET scan.

“MTBR tau is a fascinating biomarker that might reflect another aspect of tau pathology than p-tau measures,” Kaj Blennow, University of Gothenburg, Sweden, wrote to Alzforum.

MTBR-tau constitutes the bulk of neurofibrillary tangles. Measuring these tau pieces in the CSF or, ideally, blood, would enable scientists to detect when these aggregates have formed in the brain (Dec 2020 news).

Indeed, Blennow had previously reported that low CSF levels of the MTBR fragment tau368—a segment from residue 368 all the way to the C-terminus—correlated with high tau PET signal in people who had AD (Blennow et al., 2020; Mattsson-Carlgren et al., 2020). Likewise, in his first study, Horie had seen CSF MTBR-tau243 correlate tightly with tau PET and with MMSE and Clinical Dementia Rating–sum of boxes (CDR-SB) scores. Blennow told Alzforum that a low CSF tau368/t-tau ratio also correlated with higher neurofibrillary tangle density at postmortem.

Now, in a joint effort between Randall Bateman’s group at WashU and Oskar Hansson’s at Lund University, Sweden, Horie has confirmed his earlier findings in two cohorts: 219 people from the Knight AD research center at WashU and 448 from the Swedish BioFINDER study. From both, 115 participants had AD dementia, 96 had non-AD dementia, 125 had mild cognitive impairment with amyloid plaques, 167 were cognitively normal but positive for amyloid plaques, and 164 were cognitively normal with no sign of plaques. Most non-AD cases were largely primary tauopathies, including corticobasal degeneration and supranuclear palsy. Horie compared CSF concentrations of MTBR-tau243, four p-tau isoforms, Aβ40, and Aβ42 against amyloid and tau PET scans and MMSE scores. All p-tau isoforms were measured as a ratio between phosphorylated and non-phosphorylated species, e.g., p-tau217/tau217.

Which best flagged plaques and tangles? Horie declined permission to use the slide he showed at CTAD, so here is the gist in words instead. CSF p-tau217 most closely associated with amyloid PET centiloids, achieving a correlation coefficient of roughly 0.87 out of a perfect 1.0. CSF p-tau205, p-tau181, p-tau231, and MTBR-tau243 followed with coefficients of approximately 0.69, 0.67, 0.64, and 0.63. As for tangles, MTBR-tau243 best associated with tau PET SUVR, clocking a coefficient of 0.75. P-tau205 again came in second at 0.70, followed by p-tau217, p-tau231, and p-tau181 with coefficients of 0.62, 0.45, and 0.40, respectively.

Importantly, CSF MTBR-tau243 ticked up only after tangles had formed. Using two years of follow-up data available from half of the BioFINDER participants, Horie measured each biomarker’s rate of change per year in participants with plaques and tangles, those with only plaques, and controls with neither. All four p-tau species were produced at about the same rate across all three groups. In contrast, MTBR-tau243 production ramped up only in people who had plaques and tangles, not in those who only had plaques. Horie concluded that the CSF MTBR fragment specifically denoted neurofibrillary tangles in the brain.

What about cognition? CSF MTBR-tau243 correlated with MMSE scores, giving a coefficient of 0.62. This came second to tau PET, whose coefficient was 0.70. CSF p-tau205, another tau form said to rise slightly later in AD biomarker staging than p-tau231, p-tau217, or p-tau181, correlated with MMSE scores as well as did MTBR-tau243.

All told, CSF MTBR-tau243 indicates there are tangles in the brain almost as well as does a tau PET scan, Horie said. He sees MTBR-tau243 being used alongside other biomarkers to define a person's amyloid-tau-neurodegeneration status and help stage their disease.

All these markers were measured in the CSF. The field is clamoring for blood tests. How about plasma MTBR-tau243? Horie said he is trying to develop an assay for that. Henrik Zetterberg of UGot thinks it may be difficult. “These C-terminal tau fragments are present at lower concentrations than N-terminal fragments in blood, which may make them hard to detect,” he wrote. Even so, Zetterberg noted, measuring MTBR-tau in CSF looks promising.—Chelsea Weidman Burke

Comments

  1. This work is impressive. It confirms, and expands upon, prior work relating elevations in CSF MTBR-tau243 to tau PET (Horie et al., 2021), suggesting a high utility of the marker to understand the AD biological cascade. The utility of MTBR does not seem restricted to AD, though.

    Recent work led by Kanta Horie, Nicolas Barthelemy, Randall Bateman, and Chihiro Sato at Washington University in St. Louis demonstrated declines in CSF MTBR-tau275 and MTBR-tau282 in 4R tauopathies (e.g., CBD, PSPS, FTLD-MAPT, Horie et al., 2022). Together, this suggests that measuring MTBR levels will provide insight into a host of tauopathies. 

    References:

    Horie K, Barthélemy NR, Sato C, Bateman RJ. CSF tau microtubule binding region identifies tau tangle and clinical stages of Alzheimer's disease. Brain. 2021 Mar 3;144(2):515-527. PubMed. Correction.

    Horie K, Barthélemy NR, Spina S, VandeVrede L, He Y, Paterson RW, Wright BA, Day GS, Davis AA, Karch CM, Seeley WW, Perrin RJ, Koppisetti RK, Shaikh F, Lago AL, Heuer HW, Ghoshal N, Gabelle A, Miller BL, Boxer AL, Bateman RJ, Sato C. CSF tau microtubule-binding region identifies pathological changes in primary tauopathies. Nat Med. 2022 Dec;28(12):2547-2554. Epub 2022 Nov 24 PubMed.

    View all comments by Brian Gordon

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References

News Citations

  1. Plasma P-tau217 Picks Up Plaques, Tangles, Future Decline
  2. Blood Amyloid Test May Help Diagnose Alzheimer’s, but Questions Remain
  3. MTBR-243 Tau: A Fluid Biomarker for Tangles Themselves?

Paper Citations

  1. Blennow K, Chen C, Cicognola C, Wildsmith KR, Manser PT, Bohorquez SM, Zhang Z, Xie B, Peng J, Hansson O, Kvartsberg H, Portelius E, Zetterberg H, Lashley T, Brinkmalm G, Kerchner GA, Weimer RM, Ye K, Höglund K. Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology. Brain. 2020 Feb 1;143(2):650-660. PubMed.
  2. Mattsson-Carlgren N, Andersson E, Janelidze S, Ossenkoppele R, Insel P, Strandberg O, Zetterberg H, Rosen HJ, Rabinovici G, Chai X, Blennow K, Dage JL, Stomrud E, Smith R, Palmqvist S, Hansson O. Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer's disease. Sci Adv. 2020 Apr;6(16):eaaz2387. Epub 2020 Apr 15 PubMed.

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