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.

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  1. In this manuscript by Horie et al., Bateman and Sato have advanced a new immunoprecipitation (IP) mass spectrometry method to measure specific proteoforms of tau in CSF that can potentially identify pathological changes in primary tauopathies. These findings are encouraging and suggest there may be additional proteoforms of tau, some yet to be identified, that shed light on differences between the primary tauopathies.

    Interestingly, they used a two-stage IP approach. First, they depleted samples of anything binding to N-terminal and mid-domain antibodies (Tau1, HJ8.5 and HJ8.7) and then captured what was left with a C-terminal anti-tau antibody (77G7). Despite the complexity of the method, they were able to demonstrate stable and reproducible measures over four months from repeat lumbar punctures. The method measures two peptides from the microtubule binding region (MTBR) ratioed to a mid-domain tau peptide. The two MTBR peptides are both from the second repeat region that is unique to the 4-repeat form of tau. There is significant overlap between diagnostic groups, but the incorporation of this new measure, CSF MTBR-tau275/t-tau, with other CSF biomarkers could help differentiate primary tauopathies.

    Unfortunately, in the clinically diagnosed cohort (Extended Data Fig. 2), the overall levels were a bit different than the pathology-confirmed cohort and the cut-point (Extended Data Table 2; <0.00563) was not transferable. This would seem to indicate the presence of cohort effects that will need some additional studies to understand. Despite the observed cohort bias, there was still some significant lowering observed, and indications are that these new measures have potential to help differentiate primary tauopathies.

    The reason for exploring the ratio when these specific MTBR-tau peptides on their own show no differences between groups (Supplementary Fig. 1) is also intriguing, especially considering that not all MTBR peptides, or even 4R MTBR peptides, show the same lack of difference. The MTBR-tau peptides are not good biomarkers on their own, but ratioed against a mid-domain peptide that does show variation by diagnostic group, it acts to highlight differences in expression, processing, and/or clearance among proteoforms. Perhaps the authors will ratio the MTBR peptides with p-tau217 next to maximize the effects of both hyperphosphorylation and aggregation? 

    View all comments by Jeffrey Dage

  2. This is such a clever way of visualizing C-terminal tau fragments in CSF. The authors immunodepleted the more abundant N- and mid-domain tau fragments and then specifically pulled out C-terminal fragments, which are much less abundant, and then analyzed them by mass spectrometry. These C-terminal fragments seem to reflect brain tissue tau, and the resulting biomarker behaves a little bit like the Aβ42/40 ratio—in the presence of pathology, you see a reduction in relation to total-tau.

    Similar results have been seen for another C-terminal tau fragment, tau368, in Alzheimer’s disease (Blennow et al., 2020), but this is the first time that non-AD tauopathies have been examined in this way. These results show that non-AD tauopathies result in a discernible tau fluid biomarker change, the absence of which has been very puzzling before. 

    References:

    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.

    View all comments by Henrik Zetterberg

  3. This is a very important paper. The lack of positive biomarkers for corticobasal degeneration has been a major obstacle to understanding and curing this disease. CBD is often mimicked by other diseases (i.e., there are multiple causes of corticobasal syndrome), while CBD in turn can mimic other diseases. In recent years, Alzheimer’s disease-specific biomarkers have been helpful in ruling out AD as the cause of a corticobasal syndrome, but this diagnosis by exclusion has been problematic—if, for example, there is co-pathology, or if the CBS is caused by neither CBD nor AD. Recent cryo-EM studies show how tau deposited in CBD is distinctive. Now there is a fluid biomarker that can also distinguish CBD from other dementias, even other “4R-tau” diseases.

    At last, we now have Horie et al.’s result, describing a fluid biomarker that is strongly indicative of CBD more than of PSP, and distinguishes CBD from Alzheimer’s and Parkinson’s disease. The MTBRs may have even better specificity and sensitivity for FTLD-tau’s when used in conjunction with other fluid biomarkers (e.g., p-tau’s and neurofilament light chain). A future blood-based analogue would increase scalability and accessibility.

    This will enable the development and targeting of anti-CBD treatments, and the ability to study CBD in a person’s lifetime with confidence and specificity.

    The study is strengthened by the mapping of co-pathologies, the comparison of brain versus CSF, and suggested CSF thresholds for diagnosis. They also demonstrate reliability on repeat assessment, and good performance in clinically diagnosed cohorts, which are vital for the assay to be useful. Larger, longitudinal, and early stage or presymptomatic cohorts will now be able to validate the assay independently, and explore the relationship to severity and progression, as a prelude to clinical trials. The strength of correlation between brain and CSF MTBRs is, in part, driven by group differences, and correlations are weak within groups (an example of Simpson’s paradox), but this may reflect the relatively small group sizes.

    We can look forward to accelerated progress in diagnosis and clinical trials for FTLD-tau disorders, with special optimism for CBD, which cannot readily be confirmed by other means in vivo.

    View all comments by James Rowe

  4. I'm continually impressed by the wealth of information that the different MTBR species can provide. Although the increasing arsenal of ptau sites have provided additional insights, they primarily seem to reflect a response to amyloidosis. This work, along with prior work from Dr. Horie, clearly shows that MTBR can track tauopathies.

    View all comments by Brian Gordon

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  1. Finally, a Biomarker to Distinguish Primary Tauopathies?