The natural history of tau accumulation and the impact of disease stage and reference region on the magnitude and effect size of regional change

In a recent study published in the eBioMedicine, researchers performed serial tau imaging with 18F-MK6240 to detect tau accumulation in cognitively unimpaired (CU) beta-amyloid negative (Aβ−) Alzheimer’s disease (AD) patients as well as those with mild cognitive impairment [MCI] who were Aβ+ at baseline.

Background

Previous positron emission tomography (PET) imaging studies predominantly used ¹⁸F-flortaucipir to investigate the natural history of tau accumulation in AD. Longitudinal natural history data is sparse, ¹⁸F-MK6240, a high-affinity tracer for the paired helical filaments of tau in AD, is also widely used in clinical trials.

About the study

In the present study, researchers recruited participants from the Australian Dementia Network (ADNeT) and the Australian Imaging Biomarkers and Lifestyle flagship study of aging (AIBL) who completed two tau ¹⁸F-MK6240 PET scans, including a baseline and a follow-up scan before September 2022. Other inclusion criteria were ≥50 years of age, fluency in English, and a minimum of seven years of education, with no history of substance abuse or neurological or psychiatric disorders.

They evaluated the impact of the AD stage and selected brain regions on estimates of regional rates of tau accumulation. To this end, the team categorized all participants into three clinical groups, CU, MCI, and AD based on prespecified criteria. For instance, they adhered to Winblad et al. and Petersen et al. criteria to assign MCI diagnosis.

Further, the team intravenously administered 185MBq (±10%) of 18F-MK6240 for Tau PET imaging. They estimated the ¹⁸F-MK6240 standardized uptake value ratio (SUVR) across composite region of interest (ROI) and the mean annual rate of tau accumulation, i.e., change in SUVR/year for each clinical group, scaled using two reference regions: 1) cerebellar cortex; and 2) eroded subcortical white matter.

Next, the team used the MR-less CapAIBL approach to generate surface projections to visualize these changes. Finally, they estimated the spatiotemporal trajectory of tau accumulation.

Results

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The study cohort comprised 184 participants, of which 89, 44, and 51 were CU Aβ−, CU Aβ+, and cognitively impaired Aβ+, respectively. Of all cognitively impaired Aβ+, 26 and 25 had MCI and AD dementia, respectively.

Tau ¹⁸F-MK6240 PET detected tau accumulation in CU, MCI, and AD patients who were Aβ+ at baseline. The researchers observed the most pronounced tau accumulation in CU Aβ+ individuals’ inferior temporal and mesial temporal regions. However, MCI Aβ+ and AD Aβ+ individuals had the most tau accumulation in the lateral temporoparietal and mesial temporal lobe regions, respectively. Furthermore, the researchers made significant observations relevant to using tau ¹⁸F-MK6240 in AD clinical trials.

First, clinicians should take cues on ways to select the composite ROI for use in an AD therapy trial from the results of this study. For early tau detection, i.e., during the preclinical AD stage, it is best to focus on a meta-temporal composite. On the contrary, a neocortical composite ROI focusing on temporoparietal brain regions during the symptomatic AD stages might more sensitively detect tau accumulation changes.

Second, disease-modifying therapies for clearance or slowing of tau accumulation should account for the fact that after attaining very high regional tau levels at baseline, it eventually plateaus or declines in AD Aβ+ participants. Consistent with the tau PET tracer flortaucipir, the regional tau accumulation rates, as depicted in plots of regional tau SUVR, were dependent on baseline tau burden even with ¹⁸F-MK6240.

Moreover, the researchers observed that participants with high baseline tau were less than 75 years of age (relatively young) and cognitively impaired, i.e., they were living with AD. Thus, the sample size needed for clinical trial testing methods to decelerate the tau accumulation rates should account for this variance in the rates of tau accumulation by PET.

Finally, they observed that the selection of reference region for SUVR calculation also impacted the assessment of tau changes. When cortical tau was high in cognitively impaired individuals, eroded subcortical white matter reference region might be experiencing white matter tau accumulation or a spill-over effect. However, in general, the cerebellar cortex reference region performed the best.

Conclusions

To summarize, ¹⁸F-MK6240 PET scans detected tau accumulation during preclinical and symptomatic AD with an average of ~1.5 years follow-up. Its regional accumulation rate appeared to be impacted by baseline tau load and clinical AD stage. Most importantly, the results of data fitting pointed to a timespan of approximately 15 to 20 years taken to observe tau accumulation levels that manifest as AD.

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.