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

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 Braak⁰/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 R²) 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.

Keywords: Alzheimer’s disease; Amyloid-PET; Braak-staging; Conversion risk; Tau-PET.

Fig. 1

Study flowchart (A), surface rendering of Braak-stage ROIs applied to tau-PET data (B), and tau-PET classification of subjects into Braak-stages (C)

Fig. 2

Scatterplot illustrating the association between global tau-PET SUVRs, baseline global amyloid-PET (i.e., Centiloid), and annual cognitive changes of the Mini Mental State Examination (MMSE; A + B), Alzheimer’s Disease Assessment Scale Cognition 13-item scale (ADAS13; D + E), and ADNI-MEM (G + H). Standardized beta-values were derived from linear regression controlling for age, sex, education, clinical diagnosis, and the baseline score of the respective cognitive test. Bootstrapping analysis with 1000 iterations (C + F + I) revealed that bootstrapped distributions of partial R² values (i.e., explained variance in cognitive changes) were higher for global tau-PET than for global amyloid-PET. Bonferroni correction applied, adjusted alpha level = 0.017; significant p-values are marked with *; uncorrected significant p values (p < 0.05) are marked with #. Note, that the association between amyloid-PET and ADNI-MEM did not survive Bonferroni correction

Fig. 3

Tau-PET-based Braak-staging versus annual cognitive change rates for the Mini-Mental State Examination (MMSE; A), the Alzheimer’s Disease Assessment Scale Cognition 13-item scale (ADAS13; B), and the ADNI-MEM score (C). Statistics were derived from ANCOVA models controlling for age, sex, education, clinical diagnosis, global amyloid-PET (Centiloid), and the baseline score of the respective cognitive test. Post hoc Tukey tests were used in order to determine differences in cognitive changes between Braak-stage groups; ** = p < 0.01, *** = p < 0.001

Fig. 4

Rates of clinical conversion during follow-up stratified by amyloid-PET positivity, tau-PET positivity and Braak-stage group. Barplots show relative risk of clinical conversion from cognitive normal (CN) to mild cognitive impairment (MCI) or dementia, and from MCI to dementia. Note that subjects with a baseline diagnosis of dementia were excluded from this analysis, since no further diagnostic change can be observed in these participants