Long-term test-retest of cerebral [18F]MK-6240 binding and longitudinal evaluation of extracerebral tracer uptake in healthy controls and amnestic MCI patients

Vanderlinden, Greet; Mertens, Nathalie; Michiels, Laura; Lemmens, Robin; Vandenbulcke, Mathieu; Laere, Koen Van

doi:10.1007/s00259-022-05907-5

Cited by 4 publications

(16 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, cortical regions with the highest levels of extracerebral retention in this study did not coincide with such anatomical regions. Additionally, meningeal binding in FTP is less prominent than with tracers such as 18 F-MK6240, 17 therefore we argue that female slanted FTP extracerebral retention may be less likely explained by off-target meningeal binding. Another suggestion relates to defluorination of the 18 F-fluorine radioisotope.…”

Section: Discussionmentioning

confidence: 75%

“…As males have significantly higher mean ICV compared to females (t(396) ¼ 4.70, p < .001), we matched ICV to sex using a caliper of 15,000 mm 3 . The resulting matched sample consisted of 284 individuals (Supplemental Figure 2), including 142 males (mean [SD] age ¼ 76 [8] years; n [%] MCI ¼ 25 [18]) and 142 females (mean [SD] age ¼ 73 [8.6] years; n [%] MCI ¼ 13 [9]).…”

Section: Intracranial Volumementioning

confidence: 99%

“…Post-mortem studies of sex differences in neurofibrillary tangle density have suggested a localization of these sex differences in medial temporal regions. 1,2 In positron emission tomography (PET), clinically normal (CN) females exhibit greater 18 F-Flortaucipir (FTP)-PET signal than males in medial temporal regions, particularly in females with elevated amyloidbeta (Ab), which is characteristic of early tau deposition in neuropathological staging of Alzheimer's disease (AD). 3 CN females also demonstrate higher FTP-PET signal than males across many regions of the neocortex, regardless of Ab accumulation, such as the rostral middle frontal, lateral occipital, and parietal regions.…”

Section: Introductionmentioning

confidence: 99%

“…Off-target FTP signal may exist in the skull in amyloid-negative individuals, particularly in females. 17 Females have also been found to exhibit greater tau-PET signal than males in the meninges and skull across FTP, 18 F-RO948, and 18 F-MK6240 radiotracers, each with variable potency. 17,19,22 It is possible that sex-specific extracerebral signal may confound the magnitude of sex differences in cortical FTP signal.…”

Section: Introductionmentioning

confidence: 99%

“…Sample characteristics by females and males.As each cohort used different tracers and processing pipelines, Ab-PET signal was expressed dichotomously using a 1.1118 F-Florbetapir SUVR threshold in ADNI47 and a 1.18511 C-Pittsburgh Compound B DVR threshold in HABS.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Contribution of extracerebral tracer retention and partial volume effects to sex differences in Flortaucipir-PET signal

Scott,

Edwards,

Properzi

et al. 2023

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Clinically normal females exhibit higher 18F-flortaucipir (FTP)-PET signal than males across the cortex. However, these sex differences may be explained by neuroimaging idiosyncrasies such as off-target extracerebral tracer retention or partial volume effects (PVEs). 343 clinically normal participants (female = 58%; mean[SD]=73.8[8.5] years) and 55 patients with mild cognitive impairment (female = 38%; mean[SD] = 76.9[7.3] years) underwent cross-sectional FTP-PET. We parcellated extracerebral FreeSurfer areas based on proximity to cortical ROIs. Sex differences in cortical tau were then estimated after accounting for local extracerebral retention. We simulated PVE by convolving group-level standardized uptake value ratio means in each ROI with 6 mm Gaussian kernels and compared the sexes across ROIs post-smoothing. Widespread sex differences in extracerebral retention were observed. Although attenuating sex differences in cortical tau-PET signal, covarying for extracerebral retention did not impact the largest sex differences in tau-PET signal. Differences in PVE were observed in both female and male directions with no clear sex-specific bias. Our findings suggest that sex differences in FTP are not solely attributed to off-target extracerebral retention or PVE, consistent with the notion that sex differences in medial temporal and neocortical tau are biologically driven. Future work should investigate sex differences in regional cerebral blood flow kinetics and longitudinal tau-PET.

show abstract

Section: Discussionmentioning

confidence: 75%

Section: Intracranial Volumementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Contribution of extracerebral tracer retention and partial volume effects to sex differences in Flortaucipir-PET signal

Scott,

Edwards,

Properzi

et al. 2023

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

Evaluating the effect of extra-cerebral off-target binding in [F-18]MK6240 PET scans in early-stage Alzheimer’s disease

McVea,

DiFilippo,

McLachlan

et al. 2024

Imaging Neuroscience

View full text Add to dashboard Cite

[F-18]MK6240 is a PET radioligand with favorable imaging characteristics for measuring tau aggregation in Alzheimer’s disease (AD). In this study we investigated the impact of extra-cerebral off-target binding (ECB) in the meninges and sinus present in [F-18]MK6240 PET scans on quantifying tau burden in preclinical AD. Based on large cohort data from 433 [F-18]MK6240 scans acquired at the University of Wisconsin-Madison, simulations were conducted to examine the range of effects of ECB by varying the ECB profile and input radiotracer concentration curves on areas of early tau accumulation in AD. The range and patterning of ECB in the imaging cohort had high variability between participants, however, 35% revealed moderate to high meningeal signal that could influence quantification. Partial volume effects, which can lead to measured PET signal from neighboring regions influencing signal in adjacent areas of interest, were examined in the simulated images. The simulations demonstrate that signal from the sinus increases the neighboring entorhinal cortex region (ERC) signal and activity detected from the meninges can similarly influence the inferior cerebellar grey matter reference region. ECB effects from the sinus were most prevalent in our cohort, and simulations with the average ECB profile had ERC uptake (SUV) 23% higher than simulations with no ECB. Spill-in effects from the sinus, which increases the medial and ventral temporal cortex SUVR, and spill-in from the meninges into the cerebellar reference region, which leads to a reduction in global SUVR, act in opposite directions, complicating the interpretation of the derived SUVR of [F-18]MK6240 images. These simulation results quantify the effects of ECB in [F-18]MK6240 scans and introduce correction factors to minimize bias of the SUVR measure.

show abstract

Test-Retest performance of [18F]MK-6240 tau burden and relative delivery indices in cognitively normal older subjects using PET/MRI

Lois,

Fu,

Salvatore

et al. 2024

Preprint

View full text Add to dashboard Cite

Background: Accurate interpretation of quantitative PET outcomes hinges on understanding the test-retest variability (T-RT). Previous studies of the tau-PET ligand [18F]MK-6240 reported adequate T-RT performance of tau burden estimates over a short-term 21-day and over a longer-term 6-month T-RT period, primarily involving Alzheimer’s disease (AD) and cognitively normal (CN) subjects, respectively. However, several T-RT characteristics have not yet been reported, particularly in older CN (oCN) subjects. Here, we investigate the short-term T-RT performance of dynamic [18F]MK-6240 outcomes in a group largely consisting of oCN. We report T-RT for uptake in potential reference regions, for extracerebral off-target signal, and for estimates of tau burden and relative delivery indices in tau-bearing target regions. Eight participants (7 oCN, 1 AD) underwent baseline dynamic [18F]MK-6240 PET/MRI (Biograph mMR) and a retest follow-up PET/MRI scan within approximately 3 weeks. T-RT was evaluated using absolute percentage differences and interclass correlation coefficients (ICC) in three groups of regions: 1) potential reference regions using standardized-uptake-values 90-110 minutes post-injection (SUV90-110min); 2) target regions using SUV ratios (SUVR90-110min), distribution volume ratios (DVR), and relative delivery (R1); and 3) extracerebral region using SUVR90-110min. A voxel-based partial volume correction (PVC) was applied. T-RT was evaluated with and without PVC. Results: In oCN subjects, the SUV90-110min T-RT in the evaluated reference regions ranged from 6-11% (ICC > 0.9); target region T-RT was similar for SUVR90-110min (4-9%, ICC: 0.62-0.97), DVR (3-6%, ICC: 0.66-0.92), and R1 (3-11%, ICC: 0.77-0.92). PVC had minimal impact on reference region SUV90-110min T-RT, but increased target region T-RT variability (SUVR90-110min: 10-26%; DVR: 6-15%; R1: 4-14%). Extracerebral SUVR90-110min exhibited higher T-RT variability (~12%, ICC: 0.85) than other target regions (average 6%) and increased to ~15% after PVC. Conclusion: Our findings are consistent with previous reports and provide further evidence of acceptable [18F]MK-6240 T-RT in low-signal oCN subjects. Our results suggest [18F]MK-6240 is suitable for detecting early tau deposition and longitudinal changes over time, and further support the viability of [18F]MK-6240 R1 to evaluate longitudinal changes in perfusion. However, the extracerebral signal exhibited higher T-RT variability than other target and reference regions and may affect their signal.

show abstract

Long-term test-retest of cerebral [18F]MK-6240 binding and longitudinal evaluation of extracerebral tracer uptake in healthy controls and amnestic MCI patients

Cited by 4 publications

References 31 publications

Contribution of extracerebral tracer retention and partial volume effects to sex differences in Flortaucipir-PET signal

Contribution of extracerebral tracer retention and partial volume effects to sex differences in Flortaucipir-PET signal

Evaluating the effect of extra-cerebral off-target binding in [F-18]MK6240 PET scans in early-stage Alzheimer’s disease

Test-Retest performance of [18F]MK-6240 tau burden and relative delivery indices in cognitively normal older subjects using PET/MRI

Contact Info

Product

Resources

About