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Background Neuromelanin‐sensitive MRI (NM‐MRI) of the substantia nigra provides a noninvasive way to acquire an indirect measure of dopamine functioning. Despite the potential of NM‐MRI as a candidate biomarker for dopaminergic pathology, studies about its reproducibility are sparse. Purpose To assess the test–retest reproducibility of three commonly used NM‐MRI sequences and evaluate three analysis methods. Study Type Prospective study. Population A total of 11 healthy participants age between 20–27 years. Field Strength/Sequence 3.0T; NM‐MRI gradient recalled echo (GRE) with magnetization transfer (MT) pulse; NM‐MRI turbo spin echo (TSE) with MT pulse; NM‐MRI TSE without MT pulse. Assessment Participants were scanned twice with a 3‐week interval. Manual analysis, threshold analysis, and voxelwise analysis were performed for volume and contrast ratio (CR) measurements. Statistical Tests Intraclass correlation coefficients (ICCs) were calculated for test–retest and inter‐ and intrarater variability. Results The GRE sequence achieved the highest contrast and lowest variability (4.9–5.7%) and showed substantial to almost perfect test–retest ICC (0.72–0.90) for CR measurements. For volume measurements, the manual analysis showed a higher variability (10.7–17.9%) and scored lower test–retest ICCs (–0.13–0.73) than the other analysis methods. The threshold analysis showed higher test–retest ICC (0.77) than the manual analysis for the volume measurements. Data Conclusion NM‐MRI is a highly reproducible measure, especially when using the GRE sequence and CR measurements. Volume measurements appear to be more sensitive to inter/intrarater variability and variability in placement and orientation of the NM‐MRI slab. The threshold analysis appears to be the best alternative for volume analysis. Level of Evidence 2 Technical Efficacy Stage 1

A BS TRACT: α-Synucleinopathies including idiopathic Parkinson's disease, dementia with Lewy bodies and multiple systems atrophy share overlapping symptoms and pathological hallmarks. Selective neurodegeneration and Lewy pathology are the main hallmarks of α-synucleinopathies. Currently, there is no imaging biomarker suitable for a definitive early diagnosis of α-synucleinopathies. Although dopaminergic deficits detected with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) radiotracers can support clinical diagnosis by confirming the presence of dopaminergic neurodegeneration, dopaminergic imaging cannot visualize the preceding disease process, nor distinguish α-synucleinopathies from tauopathies with dopaminergic neurodegeneration, especially at early symptomatic disease stage when clinical presentation is often overlapping. Aggregated α-synuclein (αSyn) could be a suitable imaging biomarker in α-synucleinopathies, because αSyn aggregation and therefore, Lewy pathology is evidently an early driver of α-synucleinopathies pathogenesis. Additionally, several antibodies and small molecule compounds targeting aggregated αSyn are in development for therapy. However, there is no way to directly measure if or how much they lower the levels of aggregated αSyn in the brain. There is clearly a paramount diagnostic and therapeutic unmet medical need. To date, aggregated αSyn and Lewy pathology inclusion bodies cannot be assessed ante-mortem with SPECT or PET imaging because of the suboptimal binding characteristics and/or physicochemical properties of current radiotracers. The aim of this narrative review is to highlight the suitability of aggregated αSyn as an imaging biomarker in α-synucleinopathies, the current limitations with and lessons learned from αSyn radiotracer development, and finally to propose antibody-based ligands for imaging αSyn aggregates as a complementary tool rather than an alternative to small molecule ligands.

A significant number of COVID-19 patients develop 'long COVID', a condition defined by long-lasting debilitating, often neurological, symptoms. The pathophysiology of long COVID is unknown. Here we present in-vivo evidence of widespread neuroinflammation in long COVID, using a quantitative assessment, [18F]DPA-714 PET, in two long COVID patients. We reanalyzed historical data from three matched healthy control subjects, for comparison purposes. Both patients with long COVID had widespread increases in [18F]DPA-714 binding throughout the brain. Quantitative measures of binding (BPND values) were increased on average by 121% and 76%, respectively. This implicates profound neuroinflammation in the pathophysiology of long COVID.