Impulse control disorders in Parkinson’s disease: seeking a roadmap toward a better understanding

The development of an impulse control disorder (ICD) is now recognized as a potential nonmotor adverse effect of dopamine replacement therapy in Parkinson’s disease (PD). Here, recent epidemiological, neurophysiological and genetic advances are summarized to outline potential mechanisms involved. It is safe to say that dopaminergic drugs, particularly dopamine agonists, are able to induce ICDs only in a minority of patients, while the majority are somehow protected from this adverse effect. While it seems clear that men with early-onset PD are more vulnerable, other predisposing factors, such as various current or pre-PD personality traits, are a matter of debate. In terms of neurophysiological advances, one may find striking analogies to the addiction literature suggesting a causal chain beginning with certain predisposing conditions of striatal dopamine synapses, an “unnatural” increase of dopamine stimulation and a characteristic pattern of resulting functional changes in remote networks of appetitive drive and impulse control. Future prospects include potential add-on medications and the possible identification of genetic predispositions at a genome-wide scale. Functional imaging of pharmacogenetic interactions (imaging pharmacogenomics) may be an important tool on that road

Assessment of F-18-PI-2620 as a Biomarker in Progressive Supranuclear Palsy

Importance Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis. Objective: To investigate the potential of the novel tau radiotracer F-18-PI-2620 as a biomarker in patients with clinically diagnosed PSP. Design, Setting, and Participants In this cross-sectional study, participants underwent dynamic F-18-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019. Main Outcomes and Measures: Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, F-18-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex. Results Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%];mean [SD] age, 71 [6] years;mean [SD] PSP rating scale score, 38 [15];score range, 13-71) and 20 (33.3%) had PSP-non-RS (11 men [55.0%];mean [SD] age, 71 [9] years;mean [SD] PSP rating scale score, 24 [11];score range, 11-41). Ten healthy controls (2 men;mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [50.0%] with Parkinson disease and multiple system atrophy, 7 were men;mean [SD] age, 61 [8] years;of 10 [50.0%] with Alzheimer disease, 5 were men;mean [SD] age, 69 [10] years). Postmortem autoradiography showed blockable F-18-PI-2620 binding in patients with PSP and no binding in healthy controls. The in vivo findings from the first large-scale observational study in PSP with F-18-PI-2620 indicated significant elevation of tracer binding in PSP target regions with strongest differences in PSP vs control groups in the globus pallidus internus (mean [SD] distribution volume ratios: PSP-RS, 1.21 [0.10];PSP-non-RS, 1.12 [0.11];healthy controls, 1.00 [0.08];Parkinson disease/multiple system atrophy, 1.03 [0.05];Alzheimer disease, 1.08 [0.06]). Sensitivity and specificity for detection of PSP-RS vs any control group were 85% and 77%, respectively, when using classification by at least 1 positive target region. Conclusions and Relevance: This multicenter evaluation indicates a value of F-18-PI-2620 to differentiate suspected patients with PSP, potentially facilitating more reliable diagnosis of PSP. Question Can tau-positron emission tomography imaging with the novel tau radiotracer F-18-PI-2620 differentiate patients with progressive supranuclear palsy (PSP) from healthy controls and controls with disease? Findings In this cross-sectional study of 60 patients with PSP, 10 healthy controls, and 20 controls with disease, there was significantly higher F-18-PI-2620 binding in target regions of patients with PSP compared with controls regardless of disease severity. Individual patients with PSP with Richardson syndrome were separated with high sensitivity and specificity. Meaning F-18-PI-2620 tau-positron emission tomography differentiates patients with PSP from controls at the single-patient level, potentially facilitating a more reliable diagnosis. This cross-sectional study investigates the potential of novel tau radiotracer F-18-PI-2620 as a biomarker in patients with clinically diagnosed progressive supranuclear palsy

It’s all about gains: Risk preferences in problem gambling

Problem gambling is a serious socioeconomic problem involving high individual and social costs. In this article, we study risk preferences of problem gamblers including their risk attitudes in the gain and loss domains, their weighting of probabilities, and their degree of loss aversion. Our findings indicate that problem gamblers are systematically more risk taking and less sensitive toward changes in probabilities in the gain domain only. Neither their risk attitudes in the loss domain nor their degree of loss aversion are significantly different from the controls. Additional evidence for a similar degree of sensitivity toward negative outcomes is gained from skin conductance data—a psychophysiological marker for emotional arousal—in a threat-of-shock task

Inhibitory framing in hypersexual patients with Parkinson's disease. An fMRI pilot study

Hypersexuality in medicated patients with PD is caused by an increased influence of motivational drive areas and a decreased influence of inhibitory control areas due to dopaminergic medication. In this pilot study, we test a newly developed paradigm investigating the influence of dopaminergic medication on brain activation elicited by sexual pictures with and without inhibitory contextual framing. Twenty PD patients with and without hypersexuality were examined with fMRI either OFF or ON standardized dopaminergic medication. The paradigm consisted of a priming phase where either a neutral context or an inhibitory context was presented. This priming phase was either followed by a sexual or a neutral target. Sexual, compared to neutral pictures resulted in a BOLD activation of various brain regions implicated in sexual processing. Hypersexual PD patients showed increased activity compared to PD controls in these regions. There was no relevant effect of medication between the two groups. The inhibitory context elicited less activation in inhibition-related areas in hypersexual PD, but had no influence on the perception of sexual cues. The paradigm partially worked: reactivity of motivational brain areas to sexual cues was increased in hypersexual PD and inhibitory contextual framing lead to decreased activation of inhibitory control areas in PD. We could not find a medication effect and the length of the inhibitory stimulus was not optimal to suppress reactivity to sexual cues. Our data provide new insights into the mechanisms of hypersexuality and warrant a replication with a greater cohort and an optimized stimulus length in the future

Impulsivity is Associated with Increased Metabolism in the Fronto-Insular Network in Parkinson’s Disease

Front. Behav. Neurosci. 9:317. doi: 10.3389/fnbeh.2015.00317 Various neuroimaging studies demonstrated that the fronto-insular network is implicated in impulsive behavior. We compared glucose metabolism (as a proxy measure of neural activity) among 24 patients with Parkinson’s disease (PD) who presented with low or high levels of impulsivity based on the Barratt Impulsiveness Scale 11 (BIS) scores. Subjects underwent 18-fluorodeoxyglucose positron emission tomography (FDG-PET) and the voxel-wise group difference of FDG-metabolism was analyzed in Statistical Parametric Mapping (SPM8). Subsequently, we performed a partial correlation analysis between the FDG-metabolism and BIS scores, controlling for covariates (i.e., age, sex, severity of disease and levodopa equivalent daily doses). Voxel-wise group comparison revealed higher FDG-metabolism in the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and right insula in patients with higher impulsivity scores. Moreover, there was a positive correlation between the FDG-metabolism and BIS scores. Our findings provide evidence that high impulsivity is associated with increased FDG-metabolis

Risk attitudes and digit ratio (2D:4D) : evidence from prospect theory

Abstract: Prenatal androgens have organizational effects on brain and endocrine system development, which may have a partial impact on economic decisions. Numerous studies have investigated the relationship between prenatal testosterone and financial risk taking, yet results remain inconclusive.We suspect that this is due to difficulty in capturing risk preferences with expected utility based tasks. Prospect theory, on the other hand, suggests that risk preferences differ between gains, losses and mixed prospects, as well as for different probability levels. This study investigates the relationship between financial risk taking and 2D:4D, a putative marker of prenatal testosterone exposure, in the framework of prospect theory. We conducted our study with 350 participants of Caucasian and Asian ethnicities. We do not observe any significant relationship between 2D:4D and risk taking in either of these domains and ethnicities

Connectomics and molecular imaging in neurodegeneration.

Our understanding on human neurodegenerative disease was previously limited to clinical data and inferences about the underlying pathology based on histopathological examination. Animal models and in vitro experiments have provided evidence for a cell-autonomous and a non-cell-autonomous mechanism for the accumulation of neuropathology. Combining modern neuroimaging tools to identify distinct neural networks (connectomics) with target-specific positron emission tomography (PET) tracers is an emerging and vibrant field of research with the potential to examine the contributions of cell-autonomous and non-cell-autonomous mechanisms to the spread of pathology. The evidence provided here suggests that both cell-autonomous and non-cell-autonomous processes relate to the observed in vivo characteristics of protein pathology and neurodegeneration across the disease spectrum. We propose a synergistic model of cell-autonomous and non-cell-autonomous accounts that integrates the most critical factors (i.e., protein strain, susceptible cell feature and connectome) contributing to the development of neuronal dysfunction and in turn produces the observed clinical phenotypes. We believe that a timely and longitudinal pursuit of such research programs will greatly advance our understanding of the complex mechanisms driving human neurodegenerative diseases.The Molecular Imaging of Neurodegeneration Cologne (MINC) Symposium was partly funded by the Deutsche Forschungsgemeinschaft (DFG) awarded to Dr. Thilo van Eimeren (EI 892/5-1). The Deutsche Forschungsgemeinschaft (DFG) also awarded funding to Dr. Alexander Drzezga (DR442/91)

Impact of tau and amyloid burden on glucose metabolism in Alzheimer's disease.

In a multimodal PET imaging approach, we determined the differential contribution of neurofibrillary tangles (measured with [18F]AV-1451) and beta-amyloid burden (measured with [11C]PiB) on degree of neurodegeneration (i.e., glucose metabolism measured with [18F]FDG-PET) in patients with Alzheimer's disease. Across brain regions, we observed an interactive effect of beta-amyloid burden and tau deposition on glucose metabolism which was most pronounced in the parietal lobe. Elevated beta-amyloid burden was associated with a stronger influence of tau accumulation on glucose metabolism. Our data provide the first in vivo insights into the differential contribution of Aβ and tau to neurodegeneration in Alzheimer's disease