Tau positron emission tomography is a promising prognostic device in preclinical and prodromal Alzheimer’s disease

1. [¹⁸F] flortaucipir positron emission tomography (“Tau PET”) imaging predicted changes in mental status with a stronger effect size than standard prognostic markers of Alzheimer’s disease progression (measures of cortical thickness and amyloid PET) over a mean follow-up of 1.9 years.

2. Age was an effect modifier with older individuals demonstrating a faster rate of cognitive decline at any given Tau PET level.

Evidence Rating Level: 2 (Good)

Study Rundown: Alzheimer’s disease (AD) is characterized physiologically by the accumulation of tau protein and amyloid plaque in the brain, seen clinically as neurocognitive decline over time.. Tau protein-binding ligands have been identified as potential prognostic biomarkers and are thought to correlate with disease severity, although rigorous study has not been previously completed. This multicenter prospective study evaluated the predictive utility of Tau PET for assessing cognitive function over time in patients with preclinical or prodromal AD. 1431 patients in total were included. AD status was assessed clinically, as well as with magnetic resonance imaging (MRI), cerebrospinal fluid tap for amyloid-beta and neuropsychological testing. The Mini-Mental State Examination (MMSE) was used to assess changes in cognitive function over time. Patients with diagnosed AD dementia had worse MMSE scores and higher Tau PET levels at baseline than either patients with mild cognitive impairment or cognitively unimpaired controls, respectively. Tau PET was compared head-to-head with MRI measurements of cortical thickness and found to be a better predictor of decline in MMSE scores across all participants. Similar results were attained when Tau PET was compared to amyloid PET. Finally, older individuals were noted to demonstrate a more rapid decline in MMSE scores for a given Tau PET level than younger patients. These findings suggest that Tau PET may be a useful marker of disease progression over time for patients with diagnosed or preclinical AD. Some drawbacks of the study include the relatively short follow-up time (mean = 1.9 years), while AD is, in reality, a disease which may unfold over several years to decades. The MMSE is a convenient tool for assessment of cognitive function in research settings, but it does not assess functional status, which may be a more patient-important outcome. Some strengths of this study include its correlation of imaging technology with established pathologic drivers of AD progression. The findings confirm those of previous cross-sectional studies of Tau PET, and the head-to-head comparison of Tau PET against MRI and amyloid PET help to strengthen the validity of the results. Further study of the clinical usage of Tau PET in AD prognostication (i.e., feasibility, economics) are warranted.

Click to read the study in JAMA Neurology

Relevant Reading: Positron emission tomography with [¹⁸Flortaucipir] and postmortem assessment of Alzheimer’s disease neuropathologic changes.

In depth [prospective cohort study]: Patient data from centers in South Korea, Sweden and the United States were collected. Mean age of participants in this study was 71.2 years. Only patients with AD and amyloid beta-positive cerebrospinal fluid were included and compared to those with patients with mild cognitive impairment and cognitively unimpaired controls. Technical methodology for obtaining T1-weighted MRI and PET imaging is described in detail in the full manuscript. The basic statistical analysis accounted for four patient factors (age, sex, educational attainment, baseline cohort) and underwent bootstrapping with 1000 iterations to compare Tau PET to MRI and to amyloid PET respectively. The head-to-head comparisons yielded R² of 0.35 (Tau PET) vs. 0.24 (MRI), p<0.001 and R² of 0.35 (Tau PET) vs. 0.15 (MRI), p<0.001. Sensitivity analysis of specific neural regions assessed by MRI (entorhinal, Braak stages V & VI) demonstrated that Tau PET was still more strongly associated with MMSE score changes over time across all participant groups than MRI. Age, sex and APOE genotype were assessed as potential modifiers using a linear mixed-effects model; only advanced age was found to be significant (t = -2.28, p = 0.02).

Image: PD

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