Dopamine Receptors in Parkinson's Disease: A Meta-Analysis of Imaging Studies

AbstractDopamine receptors are abundant along the central nigrostriatal tract and are expressed as 5 subtypes in two receptor families. In PD, compensatory changes in dopamine receptors emerge as a consequence of the loss of dopamine nerve terminals or dopaminergic pharmacotherapy. We performed a systematic review and meta‐analysis of the available PET and single‐photon emission computed tomography studies that have investigated dopamine receptors in PD, PSP and MSA. The inclusion criteria were studies including human PET or single‐photon emission computed tomography imaging; dopamine receptor tracers (D1‐like or D2‐like) and idiopathic PD, PSP, or MSA patients compared with healthy controls. The 67 included D2‐like studies had 1925 patients. Data were insufficient for an analysis of D1‐like studies. PD patients had higher striatal binding early in the disease, but after a disease duration of 4.36 years, PD patients had lower binding values than healthy controls. Striatal D2R binding was highest in unmedicated early PD patients and in the striatum contralateral to the predominant motor symptoms. PSP and MSA‐P patients had lower striatal D2R binding than PD patients (14.2% and 21.8%, respectively). There is initial upregulation of striatal D2Rs in PD, which downregulate on average 4 years after motor symptom onset, possibly because of agonist‐induced effects. The consistent upregulation of D2Rs in the PD striatum contralateral to the predominant motor symptoms indicates that receptor changes are driven by neurodegeneration and loss of striatal neuropil. Both PSP and MSA patients have clearly lower striatal D2R binding values than PD patients, which offers an opportunity for differential diagnostics. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Societ

Imaging Impulsivity in Parkinson's Disease and the Contribution of the Subthalamic Nucleus

Taking risks is a natural human response, but, in some, risk taking is compulsive and may be detrimental. The subthalamic nucleus (STN) is thought to play a large role in our ability to inhibit responses. Differences between individuals' ability to inhibit inappropriate responses may underlie both the normal variation in trait impulsivity in the healthy population, as well as the pathological compulsions experienced by those with impulse control disorders (ICDs). Thus, we review the role of the STN in response inhibition, with a particular focus on studies employing imaging methodology. We also review the latest evidence that disruption of the function of the STN by deep brain stimulation in patients with Parkinson's disease can increase impulsivity

Neuroimaging of rapid eye movement sleep behavior disorder and its relation to Parkinson's disease

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by polysomnography-confirmed REM sleep without atonia and dream-enacting behaviors. This disorder is considered a prodromal syndrome of alpha-synucleinopathies like Parkinson's disease (PD), where it affects more than 50% of PD patients. The underlying pathology of RBD has been generally understood to involve the pontine nuclei within the brainstem. However, the complete pathophysiology beyond the brainstem remains unclear as does its relationship with PD pathology. Therefore, this review aims to survey the neuroimaging literature involving PET, SPECT, and MR imaging techniques to provide an updated understanding of the neuro-chemical, structural, and functional changes in both RBD and PD patients comorbid with RBD. This review found neuroimaging evidence that indicate alterations to the dopaminergic and cholinergic system, blood perfusion, and glucose metabolism in both RBD patients and PD patients with RBD. Beyond the brainstem, structural and functional changes were found to involve the nigrostriatal system, limbic system, and the cortex-suggesting that RBD is a multi-systemic neurodegenerative process. Future investigations are encouraged to follow RBD patients longitudinally using multimodal imaging techniques to enhance our understanding of this parasomnia disorder. Uncovering which individuals are most likely to develop an alpha-synuclein disorder in the prodromal phase will improve patient outcomes and potentially aid in the development of novel treatments for patients affected by RBD

Repetitive Transcranial Magnetic Stimulation of Dorsolateral Prefrontal Cortex Affects Performance of the Wisconsin Card Sorting Task during Provision of Feedback

Early functional neuroimaging studies of tasks evaluating executive processes, such as the Wisconsin card sorting task (WCST), only assessed trials in blocks that may contain a large amount of different cognitive processes. More recently, we showed using event-related fMRI that the dorsolateral prefrontal cortex (DL-PFC) significantly increased activity during feedback but not matching periods of the WCST, consistent with its proposed role in the monitoring of information in working memory. Repetitive transcranial magnetic stimulation (rTMS) is a method that allows to disrupt processing within a given cortical region and to affect task performance for which this region is significantly solicited. Here we applied rTMS to test the hypothesis that the DL-PFC stimulation influences monitoring of working memory without interfering with other executive functions. We applied rTMS to the right DL-PFC and the vertex (control site) in different time points of the WCST. When rTMS was applied to the DL-PFC specifically during the period when subjects were receiving feedback regarding their previous response, WCST performance deteriorated, while rTMS did not affect performance during matching either when maintaining set or during set-shifting. This selective impairment of the DL-PFC is consistent with its proposed role in monitoring of events in working memory

Dual-fuel injection fundamentals: experimental – numerical analysis into a constant-volume vessel

Abstract Dual-fuel combustion mode in compression ignition engines has been tested thoroughly, showing high potential for the reduction of emissions (especially nitric oxides and particulate matter) while keeping unchanged the fuel conversion efficiency compared with conventional Diesel engines. Controlling the reactivity of the secondary fuel is crucial for this kind of application. To this aim, a combined experimental/numerical approach is proposed in this study to provide, on one side, experimental data in controlled conditions for the calibration of the numerical models; on the other side, a numerical framework for the accurate simulation of the dual-fuel injection in engine-like operating conditions. More in detail, a constant-volume combustion vessel has been used to simulate and analyze the injection process varying the characteristic control parameters. Detailed high-resolution images of the injection and combustion processes were acquired for the validation of the numerical framework. Numerical simulations, carried out by means of the CONVERGE CFD code using a Reynolds Average Navier Stokes (RANS) approach allow for understanding the key differences between the nominal and off-design settings. Results have been compared with the experimental data in terms of liquid spray penetration. A comparison with high resolution images has also been done to prove the accuracy of the model to describe the spray evolution in terms of spray characteristics. In the provided picture, this contribution aims at demonstrating the robustness of the experimental/numerical framework that is essential for further development of such engine solution

Motor Synchronization to Rhythmic Auditory Stimulation (RAS) Attenuates Dopaminergic Responses in Ventral Striatum in Young Healthy Adults: [11C]-(+)-PHNO PET Study

Auditory-motor entrainment using rhythmic auditory stimulation (RAS) has been shown to improve motor control in healthy persons and persons with neurologic motor disorders such as Parkinson’s disease and stroke. Neuroimaging studies have shown the modulation of corticostriatal activity in response to RAS. However, the underlying neurochemical mechanisms for auditory-motor entrainment are unknown. The current study aimed to investigate RAS-induced dopamine (DA) responses in basal ganglia (BG) during finger tapping tasks combined with [11C]-(+)-PHNO-PET in eight right-handed young healthy participants. Each participant underwent two PET scans with and without RAS. Binding potential relative to the non-displaceable compartment (BPND) values were derived using the simplified reference tissue method. The task performance was measured using absolute tapping period error and its standard deviation. We found that the presence of RAS significantly improved the task performance compared to the absence of RAS, demonstrated by reductions in the absolute tapping period error (p = 0.007) and its variability (p = 0.006). We also found that (1) the presence of RAS reduced the BG BPND variability (p = 0.013) and (2) the absence of RAS resulted in a greater DA response in the left ventral striatum (VS) compared to the presence of RAS (p = 0.003), These suggest that the absence of external cueing may require more DA response in the left VS associated with more motivational and sustained attentional efforts to perform the task. Additionally, we demonstrated significant age effects on D2/3 R availability in BG: increasing age was associated with reduced D2/3 R availability in the left putamen without RAS (p = 0.026) as well as in the right VS with RAS (p = 0.02). This is the first study to demonstrate the relationships among RAS, DA response/D2/3 R availability, motor responses and age, providing the groundwork for future studies to explore mechanisms for auditory-motor entrainment in healthy elderly and patients with dopamine-based movement disorders

Serum Inflammatory Profile for the Discrimination of Clinical Subtypes in Parkinson's Disease

Background: Blood levels of immune markers have been proposed to discriminate patients with Parkinson's disease (PD) from controls. However, differences between clinical PD subgroups regarding these markers still need to be identified.Objective: To investigate whether clinical phenotypes can be predicted by the assessment of immune marker profiles in the serum of PD patients.Methods: Phenotypes of clinical PD from Tübingen, Germany (n = 145) and Toronto, Canada (n = 90) were defined regarding clinical subtype, disease onset, severity, and progression as well as presence of cognitive and/or autonomic dysfunction. A panel of serum immune markers was assessed using principal component analysis (PCA) and regression models to define the marker(s) that were associated with clinical phenotypes after adjusting for potential confounders. Findings of both centers were compared for validation. Further, a [18F] FEPPA-PET was performed in a group of patients with high and low values of candidate markers for the assessment of in vivo brain microglial activation.Results: Overall, serum immune markers did not cluster to define a pro/anti-inflammatory profile in PCA. Out of 25 markers only IL-12p40 showed a trend to discriminate between PD subgroups in both cohorts which could not be replicated by [18F] FEPPA-PET.Conclusions: Assessment of cytokines in serum does not reliably differentiate clinical PD subtypes. Accompanying subtype-irrelevant inflammation in PD, dual activity, and lack of specificity of the immune markers, the complex function of microglia, probable effects of treatment, disease stage, and progression on inflammation as well as current technical limitations may limit the usefulness of serum immune markers for the differentiation of subtypes

Regional Brain Stem Atrophy in Idiopathic Parkinson's Disease Detected by Anatomical MRI

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder characterized by the dysfunction of dopaminergic dependent cortico-basal ganglia loops and diagnosed on the basis of motor symptoms (tremors and/or rigidity and bradykinesia). Post-mortem studies tend to show that the destruction of dopaminergic neurons in the substantia nigra constitutes an intermediate step in a broader neurodegenerative process rather than a unique feature of Parkinson's disease, as a consistent pattern of progression would exist, originating from the medulla oblongata/pontine tegmentum. To date, neuroimaging techniques have been unable to characterize the pre-symptomatic stages of PD. However, if such a regular neurodegenerative pattern were to exist, consistent damages would be found in the brain stem, even at early stages of the disease. We recruited 23 PD patients at Hoenn and Yahr stages I to II of the disease and 18 healthy controls (HC) matched for age. T1-weighted anatomical scans were acquired (MPRAGE, 1 mm3 resolution) and analyzed using an optimized VBM protocol to detect white and grey matter volume reduction without spatial a priori. When the HC group was compared to the PD group, a single cluster exhibited statistical difference (p<0.05 corrected for false detection rate, 4287 mm3) in the brain stem, between the pons and the medulla oblongata. The present study provides in-vivo evidence that brain stem damage may be the first identifiable stage of PD neuropathology, and that the identification of this consistent damage along with other factors could help with earlier diagnosis in the future. This damage could also explain some non-motor symptoms in PD that often precede diagnosis, such as autonomic dysfunction and sleep disorders