Paper
- Alzforum Recommends
Ossenkoppele R, Smith R, Mattsson-Carlgren N, Groot C, Leuzy A, Strandberg O, Palmqvist S, Olsson T, Jögi J, Stormrud E, Cho H, Ryu YH, Choi JY, Boxer AL, Gorno-Tempini ML, Miller BL, Soleimani-Meigooni D, Iaccarino L, La Joie R, Baker S, Borroni E, Klein G, Pontecorvo MJ, Devous MD Sr, Jagust WJ, Lyoo CH, Rabinovici GD, Hansson O. Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease: A Head-to-Head Comparison Against Amyloid Positron Emission Tomography and Magnetic Resonance Imaging. JAMA Neurol. 2021 Aug 1;78(8):961-971. PubMed.
Recommends
Please login to recommend the paper.
Comments
Austin Hospital
This is an interesting paper with a large cohort size and two-year cognitive follow-up. The paper provides further evidence that the drivers of cognitive decline change over the course of AD, with tau burden and atrophy strongly associated with the rate of decline in the MCI and dementia phases of AD while the impact of amyloid burden declines when persons become cognitively impaired.
Clearly a positive tau PET is a good predictor of near-term clinical progression measured by decline in MMSE score. However, the value of tau PET versus other modalities for predicting decline in cognitively unimpaired (CU) persons is debatable, especially when looking longer term. Few CUs have a positive tau PET scan for binding beyond the entorhinal region, and a positive scan is rarely seen before a substantial rise in amyloid to at least 40-50 centiloids (Doré et al., 2021).
The current manuscript Figure 1, line 1, Parts E and F, shows that only a handful of the 667 CUs have an increase in tau tracer binding. Tau accumulation is a late event in preclinical AD. Consequently, recruitment for preclinical AD trials would be very difficult if a positive tau PET was required.
The Australian Imaging, Biomarkers and Lifestyle study of aging (AIBL), and many other studies using composites of cognitive tests that are sensitive for detecting subtle decline in the earliest stages of AD, have shown that amyloid PET is a very good predictor of decline in the cognitively unimpaired, and the risk is related to the amount of amyloid present (van der Kall et al., 2021). For trials that aim to recruit the earliest phases of preclinical AD, amyloid measures remain the preferred method of participant selection.
References:
Doré V, Krishnadas N, Bourgeat P, Huang K, Li S, Burnham S, Masters CL, Fripp J, Villemagne VL, Rowe CC. Relationship between amyloid and tau levels and its impact on tau spreading. Eur J Nucl Med Mol Imaging. 2021 Jul;48(7):2225-2232. Epub 2021 Jan 26 PubMed.
van der Kall LM, Truong T, Burnham SC, Doré V, Mulligan RS, Bozinovski S, Lamb F, Bourgeat P, Fripp J, Schultz S, Lim YY, Laws SM, Ames D, Fowler C, Rainey-Smith SR, Martins RN, Salvado O, Robertson J, Maruff P, Masters CL, Villemagne VL, Rowe CC. Association of β-Amyloid Level, Clinical Progression, and Longitudinal Cognitive Change in Normal Older Individuals. Neurology. 2021 Feb 2;96(5):e662-e670. Epub 2020 Nov 12 PubMed.
View all comments by Christopher RoweUniversity of Wisconsin-Madison School of Medicine and Public Health
Identifying factors that predict cognitive decline and clinical progression and characterizing the rate of expected cognitive decline for combinations of these factors remain top priorities for aging and dementia research, clinical practice, and clinical trials. In this paper, Ossenkopple and colleagues investigated the utility of tau PET imaging as a prognostic marker of MMSE change across the AD continuum (A+ unimpaired, MCI, dementia) and in subgroups of the AD continuum and A- control and A- MCI groups. The study used change in MMSE score over two years following a baseline visit that included structural MRI, an Aβ biomarker (predominantly amyloid PET), and tau PET imaging in a large, multi-cohort design including over 1,400 participants, making it one of the largest studies to investigate these associations to date. Key findings were that tau PET imaging explained more variance in MMSE change across the AD continuum and within subgroups of A+ MCI and A+ unimpaired compared to amyloid PET or structural MRI.
This addition to the literature is particularly timely considering the recent FDA approval of aducanumab (Aduhelm) in the United States, as decisions are made regarding how to identify patients who may benefit from treatment, including which diagnostic procedures will be appropriate for different patient groups.
The findings within the AD continuum largely agree with several individual cohort studies. They also agree with cross-sectional correlates between end-of-life MMSE and neuropathological staging of neurofibrillary tangles and Aβ plaques (for review, see Nelson et al., 2012). The subgroup analyses provide additional needed information about the rate of MMSE decline in various stages of AD and, importantly, how different levels of tau pathology and structural brain changes affect the rate of MMSE decline within these stages.
These results highlight how the magnitude of amyloid burden alone is a less-potent predictor of future MMSE decline in various stages of AD than are measures of tau and neurodegeneration. This type of characterization could be highly useful for clinical trial planning to better understand the expected cognitive course for individuals based on their baseline biomarker, demographic, and clinical profiles.
As the authors acknowledge, even when pooling biomarker data across multiple cohorts from around the world, there is still a lack of diversity in these samples. Diversity is greatly needed to understand to what extent these findings are representative. To this point, the paper mentions this was a mostly white, non-Hispanic sample.
Also of note, the proportion of change in MMSE variance related to tau PET and MRI differed between the main study sample and the Biofinder cohort in the A+ dementia group such that MRI explained more variance in the main study sample and tau PET explained more variance in the Biofinder sample. While there are several reasons that might explain this difference in outcomes between the two samples, these were not investigated in the current work. It will be interesting to see in future work whether these differences were driven by technical reasons (e.g., tau/amyloid tracer selection, differences in structural imaging protocols, etc.) and/or heterogeneity within the A+ dementia group between samples/studies.
Perhaps a more subtle finding was how the association between MMSE change and tau PET differed slightly between brain regions across the different disease stages. This provides some additional evidence that different tau PET spatial profiles might have more/less prognostic value in different stages of Alzheimer’s disease. This might also be relevant in the context of the age findings, where steeper MMSE decline was observed in older rather than younger participants. More in-depth analyses investigating the magnitude and spatial extent of tau PET in the context of age may have additional value when considering implementation in the clinical setting.
Lastly, this study effectively demonstrates how a biomarker panel that includes amyloid, tau, and structural brain changes has utility for predicting future cognitive decline. It is important to acknowledge that this workup is costly, and that this cost is likely prohibitive for many patients. As the authors comment, to what extent these results will translate to blood plasma biomarkers is currently unknown and actively being investigated. As these results become available, it will be important to consider the trade-offs between affordability, access, and prediction accuracy for various biomarker modalities.
References:
Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, Duyckaerts C, Frosch MP, Haroutunian V, Hof PR, Hulette CM, Hyman BT, Iwatsubo T, Jellinger KA, Jicha GA, Kövari E, Kukull WA, Leverenz JB, Love S, Mackenzie IR, Mann DM, Masliah E, McKee AC, Montine TJ, Morris JC, Schneider JA, Sonnen JA, Thal DR, Trojanowski JQ, Troncoso JC, Wisniewski T, Woltjer RL, Beach TG. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012 May;71(5):362-81. PubMed.
View all comments by Tobey BetthauserMake a Comment
To make a comment you must login or register.