Combining tau-PET and fMRI meta-analyses for patient-centered prediction of cognitive decline in Alzheimer’s disease

Abstract

Background Tau-PET is a prognostic marker for cognitive decline in Alzheimer’s disease, and the heterogeneity of tau-PET patterns matches cognitive symptom heterogeneity. Thus, tau-PET may allow precision-medicine prediction of individual tau-related cognitive trajectories, which can be important for determining patient-specific cognitive endpoints in clinical trials. Here, we aimed to examine whether tau-PET in cognitive-domain-specific brain regions, identified via fMRI meta-analyses, allows the prediction of domain-specific cognitive decline. Further, we aimed to determine whether tau-PET-informed personalized cognitive composites capture patient-specific cognitive trajectories more sensitively than conventional cognitive measures. Methods We included Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants classified as controls (i.e., amyloid-negative, cognitively normal, n = 121) or Alzheimer’s disease-spectrum (i.e., amyloid-positive, cognitively normal to dementia, n = 140), plus 111 AVID-1451-A05 participants for independent validation (controls/Alzheimer’s disease-spectrum=46/65). All participants underwent baseline 18F-flortaucipir tau-PET, amyloid-PET, and longitudinal cognitive testing to assess annual cognitive changes (i.e., episodic memory, language, executive functioning, visuospatial). Cognitive changes were calculated using linear mixed models. Independent meta-analytical task-fMRI activation maps for each included cognitive domain were obtained from the Neurosynth database and applied to tau-PET to determine tau-PET signal in cognitive-domain-specific brain regions. In bootstrapped linear regression, we assessed the strength of the relationship (i.e., partial R2) between cognitive-domain-specific tau-PET vs. global or temporal-lobe tau-PET and cognitive changes. Further, we used tau-PET-based prediction of domain-specific decline to compose personalized cognitive composites that were tailored to capture patient-specific cognitive decline. Results In both amyloid-positive cohorts (ADNI [age = 75.99±7.69] and A05 [age = 74.03±9.03]), cognitive-domain-specific tau-PET outperformed global and temporal-lobe tau-PET for predicting future cognitive decline in episodic memory, language, executive functioning, and visuospatial abilities. Further, a tau-PET-informed personalized cognitive composite across cognitive domains enhanced the sensitivity to assess cognitive decline in amyloid-positive subjects, yielding lower sample sizes required for detecting simulated intervention effects compared to conventional cognitive endpoints (i.e., memory composite, global cognitive composite). However, the latter effect was less strong in A05 compared to the ADNI cohort. Conclusion Combining tau-PET with task-fMRI-derived maps of major cognitive domains facilitates the prediction of domain-specific cognitive decline. This approach may help to increase the sensitivity to detect Alzheimer’s disease-related cognitive decline and to determine personalized cognitive endpoints in clinical trials.

Default mode network tau predicts future clinical decline in atypical early Alzheimer’s disease

“…When these imaging biomarkers were considered together in multimodal prediction models, one of the most parsimonious models included baseline tau and cortical thickness in the default mode network as the only predictors, suggesting complementary contributions of these measures to predicting clinical decline in atypical early AD. These findings are in line with previous investigations on biomarker-based prognostication in AD, which have provided converging evidence that tau PET is a superior predictor of cognitive decline compared with other measures of AD pathology and neurodegeneration including amyloid burden and gray matter atrophy in symptomatic AD patients [11][12][13][14][16][17][18][19][20] . This pattern of brain-behavior associations is also consistent with prior cross-sectional work by us and others.…”

“…While the utility of tau PET for diagnosis is established (with FDA approval in 2020), evidence has recently begun accruing to demonstrate its clinical prognostic value in early symptomatic AD. In patients with typical MCI or mild dementia due to AD, those with relatively greater cerebral tau PET signal show a relatively faster decline in cognitive test performance on the Mini Mental State Examination [11][12][13][14][15][16][17] , Addenbrooke's Cognitive Examination 18 , or neuropsychological composite scores 11,14,15,19,20 . Given the importance of the Clinical Dementia Rating (CDR) scale as a clinical outcome measure in therapeutic trials and other studies (capturing both cognitive and functional impairment), surprisingly little work has been done on tau-based prognostication of longitudinal CDR change.…”

ApoE4 and Connectivity-Mediated Spreading of Tau Pathology at Lower Amyloid Levels

“…In Alzheimer disease (AD), amyloid-β (Aβ) is thought to initiate the spreading of neurofibrillary tau pathology from temporal-lobe epicenters to connected cortical regions, driving neurodegeneration and cognitive decline . Accordingly, Aβ-targeting therapies should ideally be applied at low tau levels to efficiently attenuate the AD cascade and slow tau-related neurodegeneration and clinical progression . It is therefore crucial to determine Aβ thresholds at which tau spreading is triggered to potentially inform treatment decisions …”

Head-to-head comparison between plasma p-tau217 and Flortaucipir-PET in amyloid-positive patients with cognitive impairment

“…For a given value of p-tau217 concentration, we observed great variability in the global tau burden and regional pattern of tau-PET signal (Figure 1). Previous studies have shown that the regional patterns of tau-PET signal not only closely mirror current the clinical representation of AD related clinical syndromes 47 but also with future patterns of brain atrophy 23,24 as well as are correlated with domain-specific cognitive impairments [47][48][49] . This suggests that p-tau217 could serve as an important biomarker to assess the presence of tau pathology and disease severity, but tau-PET is advantageous for tracking regional specific tau pathology.…”