Tau-PET and in vivo Braak-staging as prognostic markers of future cognitive decline in cognitively normal to demented individuals

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Abstract

Background

To systematically examine the clinical utility of tau-PET and Braak-staging as prognostic markers of future cognitive decline in older adults with and without cognitive impairment.

Methods

In this longitudinal study, we included 396 cognitively normal to dementia subjects with ¹⁸F-Florbetapir/ ¹⁸F-Florbetaben-amyloid-PET, ¹⁸F-Flortaucipir-tau-PET and ~ 2-year cognitive follow-up. Annual change rates in global cognition (i.e., MMSE, ADAS13) and episodic memory were calculated via linear-mixed models. We determined global amyloid-PET (Centiloid) plus global and Braak-stage-specific tau-PET SUVRs, which were stratified as positive( ⁺)/negative( ⁻) at pre-established cut-offs, classifying subjects as Braak ⁰/Braak ^I+/Braak ^I–IV+/Braak ^I–VI+/Braak ^atypical+. In bootstrapped linear regression, we assessed the predictive accuracy of global tau-PET SUVRs vs. Centiloid on subsequent cognitive decline. To test for independent tau vs. amyloid effects, analyses were further controlled for the contrary PET-tracer. Using ANCOVAs, we tested whether more advanced Braak-stage predicted accelerated future cognitive decline. All models were controlled for age, sex, education, diagnosis, and baseline cognition. Lastly, we determined Braak-stage-specific conversion risk to mild cognitive impairment (MCI) or dementia.

Results

Baseline global tau-PET SUVRs explained more variance (partial R ²) in future cognitive decline than Centiloid across all cognitive tests (Cohen’s d ~ 2, all tests p < 0.001) and diagnostic groups. Associations between tau-PET and cognitive decline remained consistent when controlling for Centiloid, while associations between amyloid-PET and cognitive decline were non-significant when controlling for tau-PET. More advanced Braak-stage was associated with gradually worsening future cognitive decline, independent of Centiloid or diagnostic group ( p < 0.001), and elevated conversion risk to MCI/dementia.

Conclusion

Tau-PET and Braak-staging are highly predictive markers of future cognitive decline and may be promising single-modality estimates for prognostication of patient-specific progression risk in clinical settings.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13195-021-00880-x.

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Most cited references 45

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NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease

Clifford R. Jack, David Bennett, Kaj Blennow … (2018)

In 2011, the National Institute on Aging and Alzheimer’s Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer’s disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer’s Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer’s Association Research Framework, Alzheimer’s disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.

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An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest.

Rahul Desikan, Florent Ségonne, Bruce Fischl … (2006)

In this study, we have assessed the validity and reliability of an automated labeling system that we have developed for subdividing the human cerebral cortex on magnetic resonance images into gyral based regions of interest (ROIs). Using a dataset of 40 MRI scans we manually identified 34 cortical ROIs in each of the individual hemispheres. This information was then encoded in the form of an atlas that was utilized to automatically label ROIs. To examine the validity, as well as the intra- and inter-rater reliability of the automated system, we used both intraclass correlation coefficients (ICC), and a new method known as mean distance maps, to assess the degree of mismatch between the manual and the automated sets of ROIs. When compared with the manual ROIs, the automated ROIs were highly accurate, with an average ICC of 0.835 across all of the ROIs, and a mean distance error of less than 1 mm. Intra- and inter-rater comparisons yielded little to no difference between the sets of ROIs. These findings suggest that the automated method we have developed for subdividing the human cerebral cortex into standard gyral-based neuroanatomical regions is both anatomically valid and reliable. This method may be useful for both morphometric and functional studies of the cerebral cortex as well as for clinical investigations aimed at tracking the evolution of disease-induced changes over time, including clinical trials in which MRI-based measures are used to examine response to treatment.

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Neuropathological stageing of Alzheimer-related changes

H Braak, E Braak (1991)

Eighty-three brains obtained at autopsy from nondemented and demented individuals were examined for extracellular amyloid deposits and intraneuronal neurofibrillary changes. The distribution pattern and packing density of amyloid deposits turned out to be of limited significance for differentiation of neuropathological stages. Neurofibrillary changes occurred in the form of neuritic plaques, neurofibrillary tangles and neuropil threads. The distribution of neuritic plaques varied widely not only within architectonic units but also from one individual to another. Neurofibrillary tangles and neuropil threads, in contrast, exhibited a characteristic distribution pattern permitting the differentiation of six stages. The first two stages were characterized by an either mild or severe alteration of the transentorhinal layer Pre-alpha (transentorhinal stages I-II). The two forms of limbic stages (stages III-IV) were marked by a conspicuous affection of layer Pre-alpha in both transentorhinal region and proper entorhinal cortex. In addition, there was mild involvement of the first Ammon's horn sector. The hallmark of the two isocortical stages (stages V-VI) was the destruction of virtually all isocortical association areas. The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations.

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Author and article information

Contributors

Nicolai Franzmeier:

ORCID: http://orcid.org/0000-0001-9736-2283

Nicolai.franzmeier@med.uni-muenchen.de

Journal

Journal ID (nlm-ta): Alzheimers Res Ther

Journal ID (iso-abbrev): Alzheimers Res Ther

Title: Alzheimer's Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1758-9193

Publication date (Electronic): 12 August 2021

Publication date PMC-release: 12 August 2021

Publication date Collection: 2021

Volume: 13

Electronic Location Identifier: 137

Affiliations

[1 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, Institute, for Stroke and Dementia Research (ISD), , University Hospital, LMU Munich, ; 81377 Munich, Germany

[2 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, Department of Nuclear Medicine, , University Hospital, LMU Munich, ; 80336 Munich, Germany

[3 ]GRID grid.424247.3, ISNI 0000 0004 0438 0426, German Center for Neurodegenerative Diseases (DZNE, Munich), ; Munich, Germany

[4 ]GRID grid.452617.3, Munich Cluster for Systems Neurology (SyNergy), ; Munich, Germany

Author information

Nicolai Franzmeier http://orcid.org/0000-0001-9736-2283

Article

Publisher ID: 880

DOI: 10.1186/s13195-021-00880-x

PMC ID: 8361801

PubMed ID: 34384484

SO-VID: c7f7f32b-02d4-4bf7-9dcd-741beb0bef4b

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 18 May 2021

Date accepted : 21 July 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100003493, Gemeinnützige Hertie-Stiftung;

Funded by: Universitätsklinik München (6933)

Open Access :

Open Access funding enabled and organized by Projekt DEAL.

Custom metadata

ScienceOpen disciplines: Neurology

Keywords: alzheimer’s disease,braak-staging,tau-pet,amyloid-pet,conversion risk

Data availability:

ScienceOpen disciplines: Neurology

Keywords: alzheimer’s disease, braak-staging, tau-pet, amyloid-pet, conversion risk

Tau-PET and in vivo Braak-staging as prognostic markers of future cognitive decline in cognitively normal to demented individuals

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Supplementary Information

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Karger: Neurology and Neuroscience

Most cited references 45

NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease

An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest.

Neuropathological stageing of Alzheimer-related changes

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