Previous studies have reported substantial involvement of the noradrenergic system in Parkinson’s disease. Neuromelanin-sensitive MRI sequences and PET tracers have become available to visualize the cell bodies in the locus coeruleus and the density of noradrenergic terminal transporters. Combining these methods, we investigated the relationship of neurodegeneration in these distinct compartments in Parkinson’s disease. We examined 93 subjects (40 healthy controls and 53 Parkinson’s disease patients) with neuromelanin-sensitive turbo spin-echo MRI and calculated locus coeruleus-to-pons signal contrasts. Voxels with the highest intensities were extracted from published locus coeruleus coordinates transformed to individual MRI. To also investigate a potential spatial pattern of locus coeruleus degeneration, we extracted the highest signal intensities from the rostral, middle, and caudal third of the locus coeruleus. Additionally, a study-specific probabilistic map of the locus coeruleus was created and used to extract mean MRI contrast from the entire locus coeruleus and each rostro-caudal subdivision. Locus coeruleus volumes were measured using manual segmentations. A subset of 73 subjects had 11C-MeNER PET to determine noradrenaline transporter density, and distribution volume ratios of noradrenaline transporter-rich regions were computed. Parkinson’s disease patients showed reduced locus coeruleus MRI contrast independently of the selected method (voxel approaches: p < 0.0001, p < 0.001; probabilistic map: p < 0.05), specifically on the clinically-defined most affected side (p < 0.05), and reduced locus coeruleus volume (p < 0.0001). Reduced MRI contrast was confined to the middle and caudal locus coeruleus (voxel approach—rostral: p = 0.48, middle: p < 0.0001, and caudal: p < 0.05; probabilistic map—rostral: p = 0.90, middle: p < 0.01, and caudal: p < 0.05). The noradrenaline transporter density was lower in Parkinson’s disease patients in all examined regions (group effect p < 0.0001). No significant correlation was observed between locus coeruleus MRI contrast and noradrenaline transporter density. In contrast, the individual ratios of noradrenaline transporter density and locus coeruleus MRI contrast were lower in Parkinson’s disease patients in all examined regions (group effect p < 0.001). Our multimodal imaging approach revealed pronounced noradrenergic terminal loss relative to cellular locus coeruleus degeneration in Parkinson’s disease; the latter followed a distinct spatial pattern with the middle-caudal portion being more affected than the rostral part. The data shed first light on the interaction between the axonal and cell body compartments and their differential susceptibility to neurodegeneration in Parkinson’s disease, which may eventually direct research toward potential novel treatment approaches.

A BS TRACT: Background: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) cohorts have provided insights into the earliest neurodegenerative processes in α-synucleinopathies. Even though polysomnography (PSG) remains the gold standard for diagnosis, an accurate questionnaire-based algorithm to identify eligible subjects could facilitate efficient recruitment in research.Objective: This study aimed to optimize the identification of subjects with iRBD from the general population. Methods: Between June 2020 and July 2021, we placed newspaper advertisements, including the single-question screen for RBD (RBD1Q). Participants' evaluations included a structured telephone screening consisting of the RBD screening questionnaire (RBDSQ) and additional sleep-related questionnaires. We examined anamnestic information predicting PSG-proven iRBD using logistic regressions and receiver operating characteristic curves. Results: Five hundred forty-three participants answered the advertisements, and 185 subjects fulfilling inclusion and exclusion criteria were screened. Of these, 124 received PSG after expert selection, and 78 (62.9%) were diagnosed with iRBD. Selected items of the RBDSQ, the Pittsburgh Sleep Quality Index, the STOP-Bang questionnaire, and age predicted iRBD with high accuracy in a multiple logistic regression model (area under the curve >80%). When comparing the algorithm to the sleep expert decision, 77 instead of 124 polysomnographies (62.1%) would have been carried out, and 63 (80.8%) iRBD patients would have been identified; 32 of 46 (69.6%) unnecessary PSG examinations could have been avoided. Conclusions: Our proposed algorithm displayed high diagnostic accuracy for PSG-proven iRBD costeffectively and may be a convenient tool for research and clinical settings. External validation sets are warranted to prove reliability.

BackgroundIsolated rapid eye movement (REM) sleep behavior disorder (iRBD) cohorts have provided novel insights in the earliest neurodegenerative processes in α-synucleinopathies. Even though polysomnography remains the gold standard for diagnosis, an accurate questionnaire-based algorithm to identify eligible subjects could facilitate efficient recruitment in research.ObjectivesThis study aimed to optimize the identification of subjects with iRBD from the general population.MethodsBetween June 2020 and July 2021, we placed newspaper advertisements including the single-question screen for RBD (RBD1Q). Participants’ evaluations included a structured telephone screening consisting of the RBD screening questionnaire (RBDSQ) and additional sleep-related questionnaires. We examined anamnestic information predicting polysomnography-proven iRBD using logistic regressions and receiver operating characteristic curves.Results543 participants answered the advertisements and 185 subjects fulfilling in- and exclusion criteria were screened. Of these, 124 received polysomnography after expert selection and 78 (62.9%) were diagnosed with iRBD. Selected items of the RBDSQ, the Pittsburgh Sleep Quality Index, the STOP-Bang questionnaire, and age predicted iRBD with high accuracy in a multiple logistic regression model (area under the curve >80%). Comparing the algorithm to the sleep expert decision, 77 instead of 124 polysomnographies (62.1%) would have been carried out, while 63 (80.8%) of iRBD patients would have been identified. 32 of 46 (69.6%) unnecessary polysomnography examinations could have been avoided.ConclusionsOur proposed algorithm displayed high diagnostic accuracy for polysomnography-proven iRBD in a cost-effective manner and may be a convenient tool for application in research and clinical settings. External validation sets are warranted to prove its reliability.