Leuzy A, Smith R, Ossenkoppele R, Santillo A, Borroni E, Klein G, Ohlsson T, Jögi J, Palmqvist S, Mattsson-Carlgren N, Strandberg O, Stomrud E, Hansson O. Diagnostic Performance of RO948 F 18 Tau Positron Emission Tomography in the Differentiation of Alzheimer Disease From Other Neurodegenerative Disorders. JAMA Neurol. 2020 Aug 1;77(8):955-965. PubMed.

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  1. This is an elegant, well-powered study evaluating the diagnostic performance of the novel tau tracer [18F]RO948. The analysis was very well-executed and gave the readers a fair overview of the tracer's binding characteristics in a clinical population. The authors reported, using their impressive BioFINDER dataset, that [18F]RO948 was able to differentiate AD dementia from cognitively unimpaired elderly and other neurodegenerative conditions with remarkable accuracy (AUC > 95 percent). This article also provided a comprehensive assessment of the tracer performance in relation to CSF and MRI markers. [18F]RO948 performed better than both CSF and MRI.

    These results support that [18F]RO948 has the potential to differentiate AD dementia from other neurodegenerative conditions in research and clinical settings. The possible applications of [18F]RO948 as a surrogate endpoint for trials will be understood with the future availability of longitudinal data.

    [18F]RO948 results are in line with previous reports using [18F]Flortaucipir, which also presented great performance (AUC >~0.92-0.95) to differentiate AD dementia from other neurodegenerative diseases (Ossenkoppele et al., 2018).

    An apparent limitation was the reduced sensitivity of [18F]RO948 to detect tau accumulation confined to brain regions corresponding to early Braak stages compared to what was predicted by postmortem series (Braak and Braak, 1997). This limited sensitivity to the early detection of tau tangles was also reported for [18F]Flortaucipir (Schwarz et al., 2016; Lowe et al., 2019). Thus, more sensitive tau imaging agents, capable of capturing small increments of tau tangles, are still desirable. The possible contributions of the other second-generation tau tracers (e.g. [18F]MK-6240 and [18F]PI-2620) will be clarified by large studies across the disease continuum using these tracers.

    References:

    Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging. 1997 Jul-Aug;18(4):351-7. PubMed.

    Lowe VJ, Lundt ES, Albertson SM, Min HK, Fang P, Przybelski SA, Senjem ML, Schwarz CG, Kantarci K, Boeve B, Jones DT, Reichard RR, Tranovich JF, Hanna Al-Shaikh FS, Knopman DS, Jack CR Jr, Dickson DW, Petersen RC, Murray ME. Tau-positron emission tomography correlates with neuropathology findings. Alzheimers Dement. 2020 Mar;16(3):561-571. Epub 2020 Jan 4 PubMed.

    Ossenkoppele R, Rabinovici GD, Smith R, Cho H, Schöll M, Strandberg O, Palmqvist S, Mattsson N, Janelidze S, Santillo A, Ohlsson T, Jögi J, Tsai R, La Joie R, Kramer J, Boxer AL, Gorno-Tempini ML, Miller BL, Choi JY, Ryu YH, Lyoo CH, Hansson O. Discriminative Accuracy of [18F]flortaucipir Positron Emission Tomography for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA. 2018 Sep 18;320(11):1151-1162. PubMed.

    Schwarz AJ, Yu P, Miller BB, Shcherbinin S, Dickson J, Navitsky M, Joshi AD, Devous MD Sr, Mintun MS. Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages. Brain. 2016 May;139(Pt 5):1539-50. Epub 2016 Mar 2 PubMed.

    View all comments by Tharick Pascoal

  2. This study represents an impressive undertaking by the BioFINDER-2 team. It represents the largest RO-948 study published to date, and one of the largest studies investigating the ability of tau PET imaging to differentiate clinical phenotypes. Among the key findings, and perhaps unsurprisingly based on in vitro and first-in-human studies, RO-948 appears to be highly specific to tau aggregates observed in Alzheimer’s disease. This is best supported by the observation that across all clinical groups with rare exceptions (notably including R406w mutation carriers that are known to have mixed 3R and 4R paired-helical filamentous tau aggregates), elevated RO-948 binding was generally only observed in those that were positive for beta-amyloid. Thus RO-948 adds to a growing list of tau PET tracers like FTP, MK-6240, GTP-1, and others that seem to primarily target AD tau aggregates.

    This study undoubtedly plays a role in advancing the field’s understanding of the clinical utility of tau PET imaging, and specifically RO-948 in the context of CSF AD biomarkers and other clinical phenotypes. Comparisons between RO-948 and CSF AD biomarkers suggest that RO-948 has the highest specificity for differentiating AD dementia from controls and non-AD disorders, but differentiating the pre-dementia stages of AD from controls and non-AD disorders might be better informed by markers of beta-amyloid. While these findings might suggest that RO-948 may not be as useful in staging preclinical and prodromal disease, more work in these populations is needed to ascertain this point more conclusively. In comparison to a recent FTP study, RO-948 seems to perform comparably to FTP for differentiating AD dementia from non-AD dementia and controls.

    Of course when talking about tau tracers, it is nearly impossible to not discuss off-target binding and the potential for these ligands to have utility in non-AD tauopathies. Regarding the latter point, this study observed elevated anterior temporal FTP binding in three svPPA cases consistent with previous observations in the FTP literature. Of remarkable value to the field, these cases were also scanned with RO-948 allowing for direct comparison of FTP and RO-948 in a clinical phenotype most often associated with TDP-43 pathology. While they did observe some elevated RO-948 binding in these patients, the binding was generally lower than FTP and also differed spatially between the tracers.

    Whether or not either of these tracers are binding to underlying TDP-43 pathology or other molecular target(s) will likely need to be resolved as imaging-to-postmortem cases become available and their underlying pathology is known. Regarding off-target signal, the authors did observed extra-axial RO-948 signal near the skull and meninges in a little over 4 percent of the sample. While FTP generally does not exhibit this signal, it has been observed previously in MK-6240 studies. In the present study, the extra-axial RO-948 signal did not impact clinical classification. Also of note is that neither RO-948 nor MK-6240 exhibit off-target binding in the basal ganglia.

    This study presents a tremendous step forward for understanding the clinical and research utility of RO-948 and tau PET imaging, but there is still a clear need to develop PET ligands and/or fluid-based assays that are sensitive and selective to non-AD tauopathies and other protein aggregates observed in neurodegenerative disease. In addition to the currently available beta-amyloid and tau PET ligands, these precision tools will play a crucial role in the treatment of patients and the development of disease-modifying therapies.

    View all comments by Tobey Betthauser

  3. This is an excellent paper from the BioFINDER-2 study team. Using their large sample size, they demonstrate the high specificity of RO-948 for confirming a diagnosis of AD in patients presenting with amnestic dementia. They found that a temporal ROI (Braak I-IV) performed slightly better than a neocortical ROI (Braak V-VI), and that tau-PET performed better than CSF or MRI to distinguish patients with AD dementia from either patients with non-AD neurodegenerative disorders or elderly controls. This is a milestone paper in establishing tau-PET, and specifically RO-498 PET, as a clinically useful biomarker for patients attending memory clinics.

    Very interestingly, CSF biomarkers performed better than RO-948 PET to distinguish Aβ-positive MCI from either non-AD patients or controls, highlighting the (relative) lack of sensitivity of RO-948 for AD tauopathy in the prodromal stage of AD. Based on this data, if a single biomarker should be performed to confirm an AD diagnosis in a patient, clinicians should ask for tau-PET in demented patients but CSF in patients with MCI. 

    The key question that is not fully addressed in the paper is the reason for the superiority of CSF in MCI. Would amyloid measures (including amyloid PET) be better at that earlier stage given that tau is not consistently elevated yet ? Would fluid biomarkers be more suitable than PET measures given that fluid reflects a dynamic, ongoing, process while PET reflects the cumulative burden of past lesions (which may still be relatively low in some MCI cases) ? Longitudinal follow-up will be key here to determine which biomarker best predicts subsequent progression to dementia. 

    Improving the sensitivity of tau-PET to early tauopathy is a critical step for advancing the field. Further research should test lower thresholds in the early Braak stages ROIs, compare the sensitivity of RO-498 to other tau tracers, and evaluate how longitudinal PET data could help us detect earlier the individuals who will rapidly progress to dementia. 

    Growing evidence indicates that the different tau tracers have distinct sensitivities and off-target bindings. Head-to-head comparisons between these tracers, as the one provided here by the BioFINDER study in three svPPA patients, will definitely permit clinicians to select the most appropriate tau-PET tracer for each individual patient, according to clinical diagnosis and stage of disease. As acknowledged by the authors, final validation should be provided by a “ground truth,” which can either be clinical (dementia progression) or pathological (in PET-autopsy studies), both of which are still to be conducted for most tau PET tracers. 

    View all comments by Bernard Hanseeuw

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