NeuralCipher Research overview
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BackgroundThe locus coeruleus (LC) and its noradrenergic projections are among the earliest sites displaying pathology in Alzheimer's disease (AD) and Parkinson's disease (PD). In vivo measures of norepinephrine transporter (NET) availability with [11C]methylreboxetine ([11C]MRB) positron emission tomography (PET) and structural magnetic resonance imaging (MRI) indices of LC integrity provide complementary, but rarely integrated biomarkers.Methods13 Healthy controls (HC), individuals with 12 AD or amnestic mild cognitive impairment due to AD (AD/aMCI), and 5 patients with PD underwent [11C]MRB PET and high-resolution T1-weighted MRI. NET availability was quantified using [11C]MRB PET SUV-ratio-based binding potential (SUVr-BP) in the LC and projection regions (hippocampus, amygdala, thalamus, and prefrontal cortex). LC structural integrity was indexed by LC MRI contrast-to-noise ratio (CNR), and projection region volumes were extracted with FreeSurfer. Group differences were assessed with Kruskal-Wallis tests, and PET-MRI associations were examined using Pearson correlations with Yeo-Johnson transformation to reduce outlier influence.ResultsNo significant group-level differences in [11C]MRB PET SUVr-BP or MRI measures were observed across HC, AD/aMCI, and PD. However, LC [11C]MRB PET SUVr-BP correlated with LC MRI-CNR (r = 0.429, 95 % CI [0.082-0.684], p = 0.018). In contrast, PET-MRI associations in projection regions were weak and non-significant. Exploratory analyses confirmed expected differences in cognition, neuropsychiatric symptoms, and functional measures, most pronounced in AD/aMCI participants.ConclusionsThis proof-of-concept study demonstrates convergent multimodal assessment of LC integrity using [11C]MRB PET and LC MRI-CNR, whereas projection regions showed divergent or absent associations. These findings highlight the potential of the LC as a target for multimodal biomarker development and support further investigation of these imaging strategies in larger, longitudinal cohorts to delineate their role in detecting noradrenergic vulnerability in neurodegeneration.Significance statementThis study integrates [11C]MRB PET and MRI to examine noradrenergic integrity in Alzheimer's and Parkinson's disease. Results demonstrate strong PET-MRI convergence in the locus coeruleus, but not in projection regions, highlighting the locus coeruleus as a sensitive biomarker target and supporting multimodal imaging approaches for early detection of neurodegenerative vulnerability.
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