Imaging Cholinergic Integrity in Alzheimer’s Disease Using a Novel M4 Muscarinic PET Tracer, ¹1C-MK6884: Comparison with ¹⁸F-FDG

 

Background

Alzheimer’s disease (AD) is characterized by progressive cholinergic neuron loss, contributing to cognitive decline and motivating acetylcholinesterase therapy. ▪ While ¹⁸F-FDG PET captures global synaptic dysfunction, it does not directly measure neurotransmitter-specific changes. ▪ ¹¹C-MK-6884 is a novel PET tracer targeting M4 muscarinic receptors, enabling in vivo assessment of cholinergic synaptic integrity1. Objective: Using muscarinic receptor imaging, determine the brain topography of cholinergic loss in AD and its association with ¹⁸F-FDG PET and cognitive performance in AD.

 

Methods

Eight participants with AD underwent ¹¹C-MK6884 M4 receptor and 18F-FDG metabolism PET. Demographics AD Participants N 8 Women/Men 4/4 Age, years (mean±SD) 68.9 ± 6.4 Years of Education (mean±SD) 15 ± 1.85 MMSE (mean±SD) 15.88 ± 4.79 / 30 DemTect (mean±SD) 3.75 ± 3.28 / 18 Clock Drawing Test (mean±SD) Ace – Naming (mean±SD) 6.00 ± 3.38 / 14 9.13 ± 3.60 / 12

▪ Standardized uptake value ratios (SUVRs) were calculated for 32 cortical and subcortical regions for both tracers. Results Representative PET images from a single subject comparing 18F-FDG and 11C-MK6884 across matched axial and sagittal slices Minimal 11C-MK6884 binding in cerebellum and thalamus is consistent with low M4 receptor density in those structures Z-normalized scatterplot illustrates a near linear relationship across ROIs within subjects Greater ¹¹C-MK-6884

▪ For ¹¹C-MK6884, SUVRs were derived from 5–15 min frames using the whole cerebellum as reference. For ¹⁸F-FDG, SUVRs from 40–60 min frames were calculated using the pons as reference. SUVRs were z scored across participants.

▪ Mixed-effects models (subject random intercepts, ROI fixed effects) estimated ¹¹C-MK6884/¹⁸F-FDG differences with 95% confidence intervals.

▪ A temporal meta-ROI, defined a priori as the bilateral temporal cortex, hippocampus, and amygdala, was used to examine associations between regional M4 signal and cognitive performance.

▪ Cognitive performance was assessed with a neuropsychological battery covering memory, language, executive function, and social cognition, summarized as a composite z-score.

▪ Partial Pearson correlations (adjusted for age and education) evaluated associations between regional SUVRs and cognition.

 

Results

Representative PET images from a single subject comparing 18F-FDG and 11C-MK6884 across matched axial and sagittal slices Minimal 11C-MK6884 binding in cerebellum and thalamus is consistent with low M4 receptor density in those structures

Z-normalized scatterplot illustrates a near linear relationship across ROIs within subjects

Heat map showing subject-level Spearman correlations between ¹⁸F-FDG and ¹¹C-MK6884 across cortical ROIs, strongest in subjects 4–5

Partial correlations with cognition were significant only for ¹¹C-MK6884, stronger and near-linear in the left hemisphere, with no significant associations for ¹⁸F-FDG

Compared with ¹⁸F-FDG, 11C-MK6884 exhibited higher SUVRs in most regions, with the greatest differences in cingulate, temporal, insular, limbic, and striatal areas Thalamic and cerebellar 11C-MK6884 uptake was lower, and no differences were observed in primary cortical regions

 

Conclusions

▪¹¹C-MK6884 and ¹⁸F-FDG PET correlate strongly across cortical regions, yet ¹¹C-MK6884 highlights cholinergic specific elevations in temporal, cingulate, and striatal areas, which align with cognition, suggesting complementary roles for muscarinic receptor and metabolic imaging in AD.

▪The strong concordance between ¹¹C-MK6884 and ¹⁸F-FDG supports M4 PET as a marker of synaptic dysfunction and neurodegeneration, with potential advantages over FDG PET including a stable cerebellar reference region and possibly reduced sensitivity to metabolic confounds.