Tau Imaging with ¹⁸F-MK6240 across the Alzheimer’s Disease spectrum

Abstract

Tau deposition plays a critical role over cognition and neurodegeneration in Alzheimers disease (AD). Recent generation tracers have high target to background ratios giving a wide dynamic range that may improve sensitivity for detection of low levels of tau (Pascoal, Shin et al. 2018). Building on previous evidence, this study aims to characterize the effects of tau deposition as assessed by 18F-MK6240, in a large cohort of patients across the AD disease spectrum. A total of 464 participants, enrolled in the AIBL-ADNeT study, underwent 18F-MK6240 tau PET, 18F-NAV4964 Aβ PET, 3D structural MRI (hippocampal and whole-brain cortical volumes) and extensive neuropsychological evaluation. Participants included 266 cognitively unimpaired controls (CU), 112 patients with mild cognitive impairment (MCI), and 86 patients with probable AD dementia. Evaluation included the characterization of the pattern and degree of 18F-MK6240 tracer retention in each clinical group as well as assessment of the relationship between 18F-MK6240 and age, Aβ imaging, brain volumetrics and cognition in each of the clinical groups. Standard uptake value ratios (SUVR) were estimated in four predefined composite regions of interest (ROIs), reflecting the stereotypical progression of tau pathology in the brain: 1. Mesial-temporal (Me), 2. Temporoparietal (Te), 3. Remainder of neocortex (R), 4. A temporal meta-region termed metaT+. 18F-MK6240 retention was higher in AD patients compared with all other diagnostic groups, with 18F-MK6240 distinguishing patients with AD from CU individuals, with the highest effect size obtained in the amygdala (Cohen d: 2.07), and Me (Cohen d: 1.99). When considering Aβ status, 18F-MK6240 not only was able to distinguish between Aβ+ AD patients and Aβ- CU (Cohen d: 2.23), but also between Aβ+ and Aβ- CU (Cohen d: 1.32). In Aβ- CU, 18F-MK6240 retention in Me showed a slow age-related increase, while 18F-MK6240 retention was higher in younger elderly Aβ+ AD patients compared to their older counterparts. There was a sigmoidal relationship between subthreshold tau and Aβ, providing evidence for a very slow but steady increase in subthreshold tau prior to a fast increase in cortical Aβ. Moreover, a non-linear relationship between Aβ and tau suggest that detectable cortical Aβ precedes detectable cortical tau. While age was the main predictor of cognitive decline in CU, and Aβ and hippocampal volume in MCI, the main predictor of cognitive decline in the AD group was tau. High tau was associated with faster cognitive decline and clinical progression in the CU and MCI groups. This large study provides further evidence that 18F-MK6240 discriminates CU from AD and, most importantly, Aβ+ from Aβ- CU individuals with high effect sizes, suggesting that 18F-MK6240 can detect lower tau levels than earlier tau tracers, crucial for early detection of tau deposition as well as tracking small tau changes over time. In conclusion, identification of regional cortical tau deposition has critical diagnostic and prognostic implications and should become a standard tool to identify individuals at risk, as well as outcome measure, in both anti-Aβ and anti-tau trials.

The association of age-related and off-target retention with longitudinal quantification of [18F]MK6240 tau-PET in target regions

“…Previous cross-sectional studies have already shown that indices of tau load made using [ 18 F]MK6240 are amenable to simplified tissue ratio methods using data acquired 90-110 minutes post-injection( 4,7 ). However, questions remain regarding the suitability of the reference region for longitudinal tracer quantification due to the bias often inherent to SUVR data( 10,11 ). This is of paramount importance because [ 18 F]MK6240 has been used in clinical trial settings to capture longitudinal changes in tau tangle pathology( 27 ).…”

“…As shown in post-mortem data, the tracer does not seem to bind to tau aggregates in non-AD tauopathies (5,8), except in rare frontotemporal dementia mutations associated with brain deposition of NFT (9). [ 18 F]MK6240 allows for the differentiation between cognitively unimpaired (CU), mild cognitive impairment (MCI), and AD subjects (4,10).…”

“…As shown in post-mortem data, the tracer does not seem to bind to tau aggregates in non-AD tauopathies( 5,8 ), except in rare frontotemporal dementia mutations associated with brain deposition of NFT( 9 ). [ 18 F]MK6240 allows for the differentiation between cognitively unimpaired (CU), mild cognitive impairment (MCI), and AD subjects( 4,10 ). Furthermore, [ 18 F]MK6240 has been shown to recapitulate in vivo the tau pathologic stages, proposed via post-mortem studies by Braak and colleagues( 11,12 ).…”

“…Those are regions also observed using first-generation tau-PET tracers such as the substantia nigra ( 13 ). However, there is a much greater off-target retention of [ 18 F]MK6240 in the meninges( 4,10 ), and it is currently the main concern for an accurate quantification of NFT using this tracer.…”

Elementary Pathophysiology, Treatment, Risk Factor of Alzheimer’s Disease

“…In the brains of Alzheimer's patients, hyperphosphorylated tau causes tubulin polymerization capacity loss and configuration changes [21][22], As a result, microtubule function is disrupted [23]. Tau-tau interactions and polymerization result in insoluble PHFs and straight filaments (SFs), which form intraneuronal fibrillar deposits known as NFTs [24]. NFTs promote cell dysfunction by reducing the number of synapses, causing neurotoxicity [25].…”