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Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine‐related changes in large‐scale brain network dynamics and its implications in clinical features. We pooled data from two disease‐control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting‐state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single‐photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age‐ and sex‐matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age‐ and sex‐matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent 18F‐DOPA‐positron emission tomography (PET) imaging. The striatal synthesis capacity of 18F‐DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre‐processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k‐means clustering were conducted separately for each cohort to derive dFC states (reemerging intra‐ and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L‐dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large‐scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD. Practitioner Points: Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD‐specific changes in dynamic functional connectivity.Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state.Results only in the PPMI cohort suggest striatal dopamine availability influences large‐scale network dynamics that are relevant in motor control. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is currently diagnosed largely on the basis of expert judgement with neuroimaging serving only as a supportive tool. In a recent study, we identified a hypometabolic midbrain cluster, which includes parts of the substantia nigra, as the best differentiating metabolic feature for PD- patients based on group comparison of [18F]-fluorodeoxyglucose ([18F]-FDG) PET scans. Longitudinal analyses confirmed progressive metabolic changes in this region and, an independent study showed great potential of nigral metabolism for diagnostic workup of parkinsonian syndromes. In this study, we applied amachine learning approach to evaluatemidbrainmetabolismmeasured by [18F]-FDG PET as a diagnostic marker for PD. In total, 51 mid-stage PD- patients and 16 healthy control subjects underwent high-resolution [18F]-FDG PET. Normalized tracer update values of the midbrain cluster identified by between-group comparison were extracted voxel-wise from individuals' scans. Extracted uptake values were subjected to a random forest feature classification algorithm. An adapted leave-one-out cross validation approach was applied for testing robustness of the model for differentiating between patients and controls. Performance of the model across all runs was evaluated by calculating sensitivity, specificity and model accuracy for the validation data set and the percentage of correctly categorized subjects for test data sets. The randomforest feature classification of voxel-based uptake values from the midbrain cluster identified patients in the validation data set with an average sensitivity of 0.91 (Min: 0.82, Max: 0.94). For all 67 runs, in which each of the individuals was treated once as test data set, the test data set was correctly categorized by our model. The applied feature importance extraction consistently identified a subset of voxels within the midbrain cluster with highest importance across all runs which spatially converged with the left substantia nigra. Our data suggest midbrain metabolism measured by [18F]-FDG PET as a promising diagnostic imaging tool for PD. Given its close relationship to PD pathophysiology and very high discriminatory accuracy, this approach could help to objectify PD diagnosis and enable more accurate classification in relation to clinical trials, which could also be applicable to patients with prodromal disease. [ABSTRACT FROM AUTHOR]

Objective: While variations in the first intron of the fat mass and obesityassociated gene (FTO, rs9939609 T/A variant) have long been identified as a major contributor to polygenic obesity, the mechanisms underlying weight gain in risk allele carriers still remain elusive. On a behavioral level, FTO variants have been robustly linked to trait impulsivity. The regulation of dopaminergic signaling in the meso-striatal neurocircuitry by these FTO variants might represent one mechanism for this behavioral alteration. Notably, recent evidence indicates that variants of FTO also modulate several genes involved in cell proliferation and neuronal development. Hence, FTO polymorphisms might establish a predisposition to heightened trait impulsivity during neurodevelopment by altering structural meso-striatal connectivity. We here explored whether the greater impulsivity of FTO variant carriers was mediated by structural differences in the connectivity between the dopaminergic midbrain and the ventral striatum. Methods: Eighty-seven healthy normal-weight volunteers participated in the study; 42 FTO risk allele carriers (rs9939609 T/A variant, FTO+ group: AT, AA) and 39 non-carriers (FTO-group: TT) were matched for age, sex and body mass index (BMI). Trait impulsivity was assessed via the Barratt Impulsiveness Scale (BIS-11) and structural connectivity between the ventral tegmental area/substantia nigra (VTA/SN) and the nucleus accumbens (NAc) was measured via diffusion weighted MRI and probabilistic tractography. Results: We found that FTO risk allele carriers compared to non-carriers, demonstrated greater motor impulsivity (p = 0.04) and increased structural connectivity between VTA/SN and the NAc (p< 0.05). Increased connectivity partially mediated the effect of FTO genetic status on motor impulsivity. Conclusion: We report altered structural connectivity as one mechanism by which FTO variants contribute to increased impulsivity, indicating that FTO variants may exert their effect on obesity-promoting behavioral traits at least partially through neuroplastic alterations in humans. [ABSTRACT FROM AUTHOR]

Excessive food intake and reduced physical activity have long been established as primary causes of obesity. However, the underlying mechanisms causing this unhealthy behavior characterized by heightened motivation for food but not for physical effort are unclear. Despite the common unjustified stigmatization that obesity is a result of laziness and lack of discipline, it is becoming increasingly clear that high-fat diet feeding and obesity cause alterations in brain circuits that are critical for the control of motivational behavior. In this mini-review, we provide a comprehensive overview of incentive motivation, its neural encoding in the dopaminergic mesolimbic system as well as its metabolic modulation with a focus on derangements of incentive motivation in obesity. We further discuss the emerging field of metabolic interventions to counteract motivational deficits and their potential clinical implications. [ABSTRACT FROM AUTHOR]

Dynamic contrast enhanced MRI (DCE-MRI) is a useful method to monitor therapy assessment in malignancies but must be reliable and comparable for successful clinical use. The aim of this study was to evaluate the inter- and intrarater reproducibility of DCE-MRI in lung cancer. At this IRB approved single centre study 40 patients with lung cancer underwent up to 5 sequential DCE-MRI examinations. DCE-MRI were performed using a 3.0T system. The volume transfer constant Ktrans was assessed by three readers using the two-compartment Tofts model. Inter- and intrarater reliability and agreement was calculated by wCV, ICC and their 95% confident intervals. DCE-MRI allowed a quantitative measurement of Ktrans in 107 tumors where 91 were primary carcinomas or intrapulmonary metastases and 16 were extrapulmonary metastases. Ktrans showed moderate to good interrater reliability in overall measurements (ICC 0.716–0.841; wCV 30.3–38.4%). Ktrans in pulmonary lesions ≥ 3 cm showed a good to excellent reliability (ICC 0.773–0.907; wCV 23.0–29.4%) compared to pulmonary lesions < 3 cm showing a moderate to good reliability (ICC 0.710–0.889; wCV 31.6–48.7%). Ktrans in intrapulmonary lesions showed a good reliability (ICC 0.761–0.873; wCV 28.9–37.5%) compared to extrapulmonary lesions with a poor to moderate reliability (ICC 0.018–0.680; wCV 28.1–51.8%). The overall intrarater agreement was moderate to good (ICC 0.607–0.795; wCV 24.6–30.4%). With Ktrans, DCE MRI offers a reliable quantitative biomarker for early non-invasive therapy assessment in lung cancer patients, but with a coefficient of variation of up to 48.7% in smaller lung lesions. [ABSTRACT FROM AUTHOR]