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Introduction: Healthcare-associated infections are the main reported adverse event in healthcare, with significant economic costs that include those caused by medical malpractice claims. In Italy, there is a fault-based compensation system, but in this specific field, the burden of proof on the hospitals is particularly heavy. Hence, we aimed to verify the economic impact of the inclusion of experts in hospital infection surveillance into internal committees for claims assessment and to evaluate what would have been the economic impact of a mandatory no-fault system rather than the current system., Materials and Methods: We compared two 4-year periods (T1: 2015-2018 and T2: 2019-2022), investigating the medical malpractice claims related to healthcare-associated infections in a large tertiary public hospital in Florence, Italy. Decisions of the internal committee, evolutions of the claims after the decision, and conclusions of the claims were registered. No-fault system simulations were used to evaluate the cost-effectiveness of the model., Results: We observed a decrease in the number of claims after the implementation of infection prevention and control (IPC) experts into the committee (a 24% decrease in rejections and a 19% increase in admissions). We found a 6806.98 euros difference (not statistically significant) in compensations in T1 and T2. Moreover, our simulations found that a no-fault compensation system - if alternative to the traditional fault-based approach - could lead to gains or losses for the plaintiffs depending on the approach chosen. (We observed a 52% mean decrease in compensations with a 150000 euros maximal indemnity and a 134% mean increase with an indemnity tailored considering also life expectancy)., Discussion: Introducing experts in IPC into hospital committees for medico-legal claims management has proven to be cost-effective, offering a no-fault compensation system as an alternative to the traditional fault-based approach, supported by a properly evaluated maximal indemnity. Due to the limitations of our models, multicentric studies are recommended to verify our results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Grassi, Grazzini, Guerini, Bertana, Pompeo, Paolini, Niccolini, Focardi and Pinchi.)

Background: The hospital discharge process plays a key role in patient care. Careggi Re-Engineered Discharge (CaRED) aimed at establishing a meaningful relationship among general practitioners (GPs) and patients, throughout the discharge process., Objective: The aim is to describe the activities and results in the period 2014-17 of the CaRED., Methods: CaRED is a restructured discharge protocol, which foresees a different, more direct form of communication between hospital and GPs, enabled by an ad hoc electronic medical record. The 30-day hospital readmission rate and/or accesses to the emergency department were evaluated as proxy for effective communication. A pre-post survey was launched to assess the GPs' perceived quality, and patient and family satisfaction., Results: A total of 1549 hospitalizations were included, respectively, 717 in the pre and 832 in the post-intervention period. The 30-day hospital readmission rate decreased significantly in the post-intervention period (14.4% vs. 19.4%, χ2(1) = 8.03, P < 0.05).Eighty-two and 52 GPs participated, respectively, in the pre- and post-survey. In the post-phase the percentage of GPs declaring the discharge letter facilitated the communication on the admission causes (χ2(1) = 0.56, P = 0.03) and on what to do if conditions change (χ2(31) = 19.0, P < 0.01) significantly increased, as well as the perception of an easier contact with the hospitalist (χ2(3) = 19.6, P < 0.01).Two-hundred-eighty and 282 patients were enrolled in the pre- and post-survey. The level of understanding of key parts of the discharge letter (reason for hospitalization, post-discharge therapy, follow-up examinations and how to contact the hospital ward) improved significantly (P < 0.01)., Conclusions: CaRED significantly improved the discharge process and became a benchmark for local improvements in communication patterns with GPs., (© The Author(s) 2022. Published by Oxford University Press on behalf of International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction. The SARS-CoV-2 pandemic has involved healthcare workers (HCWs) both as caregivers and as patients. This study is a retrospective cross-sectional analysis of the HCWs working in a third-level hospital in Central Italy who were infected with COVID-19 from March 2020 to April 2021. This research aims at identifying the physical and mental health outcomes of HCWs infected with COVID-19 who returned to work after the infection, the determinants of those outcomes, such as age and sex, and the identification of possible vulnerable professional groups. Methods. A questionnaire about the acute illness, the experience of returning to work, and health perceptions after the disease was administered to 427 healthcare workers 3 months after recovering from the SARS-CoV-2 infection. Results. The majority interviewed (84.5%) reported symptoms at the time of the positive test, with no significant differences regarding age or sex, while a significant difference in the mean age was found regarding hospitalization (p < 0.001). At 3 months after the infection, females (p = 0.001), older workers (p < 0.001), and healthcare assistants (p < 0.001) were more likely to report persistent symptoms. Sex (p = 0.02) and age (p = 0.006) influenced the quality of sleep after the infection. At work, the nurses group reported increase in workload (p = 0.03) and worse relationships (p = 0.028). At 3 months after the infection, female workers perceived worse physical (p = 0.002) and mental (p < 0.001) health status according to the SF-12. A negative correlation was found between age and PCS score (p < 0.001) but not MCS score (p = 0.86). A significant difference in PCS score was found between nurses and physicians (p = 0.04) and between residents and all other groups (p < 0.001). Finally, the group of workers reporting sleep alterations showed lower PCS and MCS scores (p < 0.001) and working relationships had an impact on MCS scores (p < 0.001). Conclusions. Age, sex, and type of job had an impact on physical and mental outcomes. Organizing specific interventions, also tailored to professional sub-groups, should be a target for healthcare systems to protect and boost the physical and mental health of their workers.

Marine protected areas (MPAs) socio-ecological effectiveness depends on a number of management and governance elements, among which stakeholder engagement and community support play key roles. Collaborative conservation initiatives that engage stakeholders in action research and knowledge co-production processes can enhance management and governance of MPAs. To design effective strategies aimed at reconciling biodiversity conservation and management of sustainable human uses, it is key to assess how local communities respond to such initiatives and identify the set of contextual factors, institutional, local and individual, potentially affecting these responses. This paper presents the approach and results of one such initiative, spanning 6 EU countries and 11 MPAs in the Mediterranean Sea, focusing on small-scale fishers as key MPA users. Through a collaborative project, managers and fishers agreed upon specific governance interventions (e.g. increasing stakeholder engagement, engaging fishers in monitoring activities, reducing fishing efforts) to be implemented in each MPA for one year. Structured surveys queried: MPA managers on the MPA context, governance structure, feasibility and effectiveness of the tested interventions; and small-scale fishers on their perceptions of the impact of the tested interventions on a set of 9 socio-ecological variables (e.g. amount of fish caught, level of participation in decision-making, support for the MPA). Results revealed that the interventions tested were relatively feasible, effective and cost-effective. Fishers reported positive perceptions of the interventions for the 9 variables considered, especially for level of support for the MPA and for those associated with aspects of governance. Proportional odds models highlighted perceived effects are maximized under certain institutional, local and individual circumstances (e.g. old MPAs, small fisher communities, and fishers with a high proportion of income from fisheries). Findings highlight that employing good governance processes involving stakeholders may rapidly generate improved local support for conservation and provide insights for potential leverage points upon which to act to maximize perceived effectiveness and enhance support toward MPAs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Preclinical studies suggest a link between cAMP/PKA signalling, phosphodiesterase 4 (PDE4) expression and excessive daytime sleepiness (EDS). Here, we investigated in vivo the association between PDE4 expression and EDS in Parkinson's disease (PD) patients using [ 11 C]rolipram PET and MR imaging., Methods: Eighteen participants, 12 PD and 6 healthy controls, underwent one [ 11 C]rolipram PET and a multi-modal MRI scan. Probabilistic tractography was performed on subjects' diffusion data to functionally parcellate the striatum according with projections to limbic cortical areas. The severity of EDS was assessed using the Epworth Sleepiness Scale (ESS). To assess PDE4 expression in PD patients with EDS, the PD cohort was divided according to the presence (n = 5) or absence (n = 7) of EDS, defined using validated cut-off of score ≥10 on the ESS as score ≥10 on the ESS., Results: PD patients with EDS showed significantly increased [ 11 C]rolipram volume of distribution (V T ) in the caudate (P = 0.029), hypothalamus (P = 0.013), hippocampus (P = 0.036) and limbic striatum (P = 0.030) compared to patients without EDS. Furthermore, higher ESS scores correlated with increased [ 11 C]rolipram V T in the caudate (r = 0.77; P = 0.003), hypothalamus (r = 0.84; P = 0.001), hippocampus (r = 0.81; P = 0.001) and limbic subdivisions of the striatum (r = 0.80; P = 0.003)., Conclusion: Our findings translate into humans preclinical data indicating that EDS is associated with elevated PDE4 in regions regulating sleep. The severity of EDS in PD was associated with elevated PDE4 expression; thus, suggesting a role of PDE4 in the pathophysiology of EDS in PD., (Copyright © 2019. Published by Elsevier Ltd.)

Over the course of the disease, about 80% of Parkinson's disease patients will develop cognitive impairment. However, predictive factors associated with cognitive decline are still under investigation. Here, we investigated which clinically available markers are predictive of cognitive impairment in a cohort of early drug-naïve Parkinson's disease patients. 294 drug-naïve Parkinson's disease patients, who were cognitively normal at baseline, were recruited from the Parkinson's Progression Markers Initiative. At 36-month follow-up, patients were diagnosed with cognitive impairment according to two levels: Level 1 diagnosis was defined as MoCA < 26 and Level 2 diagnosis was defined as MoCA < 26, alongside an impaired score on at least two neuropsychological tests. Predictive variables with a validated cut-off were divided into normal or abnormal measures, whilst others were divided into normal or abnormal measures based on the decile with the highest power of prediction. At 3 years' follow-up, 122/294 Parkinson's disease (41.5%) patients had cognitive decline. We found that age at Parkinson's disease onset, MDS-UPDRS Part-III, Hopkin's Learning Verbal Test-Revised Recall, Semantic Fluency Test and Symbol Digit Modalities Test were all predictors of cognitive decline. Specifically, age at Parkinson's disease onset, Semantic Fluency Test and symbol Digit Modalities Test were predictors of cognitive decline defined by Level 2. The combination of three abnormal tests, identified as the most significant predictors of cognitive decline, gave a 63.6-86.7% risk of developing cognitive impairment defined by Level 2 and Level 1 criteria, respectively, at 36-month follow-up. Our findings show that these clinically available measures encompass the ability to identify drug-naïve Parkinson's disease patients with the highest risk of developing cognitive impairment at the earliest stages. Therefore, by implementing this in a clinical setting, we can better monitor and manage patients who are at risk of cognitive decline.

Background: Non-motor symptoms are common aspects of Parkinson's disease (PD) occurring even at the prodromal stage of the disease and greatly affecting the quality of life. Here, we investigated whether non-motor symptoms burden was associated with cortical thickness and subcortical nuclei volume in PD patients., Methods: We studied 41 non-demented PD patients. Non-motor symptoms burden was assessed using the Non-Motor Symptoms Scale grading (NMSS). Cortical thickness and subcortical nuclei volume analyses were carried out using Free-Surfer. PD patients were divided into two groups according to the NMSS grading: mild to moderate (NMSS: 0-40) and severe (NMSS: ≥ 41) non-motor symptoms., Results: Thalamic atrophy was associated with higher NMSQ and NMSS total scores. The non-motor symptoms that drove this correlation were sleep/fatigue and gastrointestinal tract dysfunction. We also found that PD patients with severe non-motor symptoms had significant thalamic atrophy compared to the group with mild to moderate non-motor symptoms., Conclusions: Our findings show that greater non-motor symptom burden is associated with thalamic atrophy in PD. Thalamus plays an important role in processing sensory information including visceral afferent from the gastrointestinal tract and in regulating states of sleep and wakefulness.

Background: Recent work has shown loss of phosphodiesterase 10A levels in middle-stage and advanced treated patients with PD, which was associated with motor symptom severity., Objectives: To assess phosphodiesterase 10A levels in early PD and compare with loss of dopamine transporter as markers of disease burden., Methods: Seventy-eight subjects were included in this study (17 early de novo, 15 early l-dopa-treated, 24 moderate-advanced l-dopa-treated patients with PD, and 22 healthy controls). All participants underwent [ 11 C]IMA107 PET, [ 11 C]PE2I PET, and 3-Tesla MRI scan., Results: Early de novo PD patients showed loss of [ 11 C]IMA107 and of [ 11 C]PE2I binding in caudate and putamen (P < 0.001); early l-dopa-treated PD patients showed additional loss of [ 11 C]IMA107 in the caudate (P < 0.001; annual decline 3.6%) and putamen (P < 0.001; annual decline 2.8%), but loss of [ 11 C]PE2I only in the putamen (P < 0.001; annual decline 6.8%). Lower [ 11 C]IMA107 correlated with lower [ 11 C]PE2I in the caudate (rho = 0.51; P < 0.01) and putamen (rho = 0.53; P < 0.01). Longer disease duration correlated with lower [ 11 C]IMA107 in the caudate (rho = -0.72; P < 0.001) and putamen (rho = -0.48; P < 0.01), and with lower [ 11 C]PE2I only in the putamen (rho = -0.65; P < 0.001). Higher burden of motor symptoms correlated with lower [ 11 C]IMA107 in the caudate (rho = -0.42; P < 0.05) and putamen (rho = -0.41; P < 0.05), and with lower [ 11 C]PE2I only in the putamen (rho = -0.69; P < 0.001)., Conclusion: Our findings demonstrate loss of phosphodiesterase 10A levels very early in the course of PD and is associated with the gradual and progressive increase of motor symptoms. Phosphodiesterase 10A imaging shows similar potential with dopamine transporter imaging to follow disease progression. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Background: The underlying pathophysiology of dysphagia is multifactorial and evidence clarifying the precise mechanisms are scarce. Dysfunction in dopamine-related and non-dopamine-related pathways, changes in cortical networks related with swallowing and peripheral mechanisms have been implicated in the pathogenesis of dysphagia. We aimed at investigating whether dysphagia is associated with presynaptic dopaminergic deficits, faster motor symptom progression and cognitive decline in a population of early drug-naïve patients with Parkinson's disease., Methods: By exploring the database of Parkinson's Progression Markers Initiative we identified forty-nine early drug-naïve Parkinson's disease patients with dysphagia. Dysphagia was identified with SCOPA-AUT question 1 (answer regularly) and was assessed with MDS-UPDRS Part-II, Item 2.3 (Chewing and Swallowing). We compared Parkinson's disease patients with dysphagia to Parkinson's disease patients without dysphagia, and investigated differences in striatal [123I]FP-CIT single photon emission computed tomography levels. Using Cox proportional hazards analyses, we also evaluated whether dysphagia can predict motor deterioration and cognitive dysfunction., Results: Parkinson's disease patients with dysphagia, harbored a greater deterioration regarding motor and non-motor symptoms and decreased [123I]FP-CIT binding when compared with patients without dysphagia. Higher burden of dysphagia (MDS-UPDRS-II, item 2.3) was correlated with lower [123I]FP-CIT uptakes within the striatum (rs = -0.157; P = 0.002) and the caudate (rs = -0.156; P = 0.002). The presence of dysphagia was not a predictor of motor progression (Hazard ratio [HR]: 1.143, 95% confidence interval [CI]: 0.848-1.541; P = 0.379) or cognitive decline (HR: 1.294, 95% CI: 0.616-2.719; P = 0.496)., Conclusions: Dysphagia is associated with decreased presynaptic dopaminergic integrity within caudate and greater motor and non-motor symptoms burden in early drug-naïve PD., Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: GP is a paid employee of F. Hoffmann-La Roche Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products to declare.

Introduction: Speech difficulties are a common debilitating feature of Parkinson's disease and we aimed to investigate whether speech difficulties are associated with striatal dopaminergic deficits and faster disease progression., Methods: Using the Parkinson's Progression Markers Initiative database, 143 early de novo Parkinson's disease patients with speech difficulties were identified and matched 1:1 with 143 Parkinson's disease patients without speech difficulties for age, disease duration and motor symptom severity. We investigated differences in clinical features and striatal [ 123 I]FP-CIT single photon emission computed tomography (SPECT) uptake in Parkinson's disease patients with and without speech difficulties. Cox proportional hazards analysis was carried out to investigate whether speech difficulties were predictive of a faster motor progression and cognitive decline., Results: Speech difficulties were more common in patients with an akinetic-rigid motor phenotype compared to those with a tremor-dominant phenotype. Parkinson's disease patients with speech difficulties had lower resting tremor (P = 0.027), higher autonomic dysfunction (P = 0.034), increased daytime sleepiness (ESS; P = 0.048), and a higher prevalence of REM sleep behaviour disorder (RBD) symptoms (P = 0.007) compared to those without speech difficulties. Parkinson's disease patients with speech difficulties had significantly lower [ 123 I]FP-CIT uptake in the striatum (P < 0.001), caudate (P = 0.003) and putamen (P = 0.003) compared to those without speech difficulties. The presence of speech difficulties was a predictor of cognitive decline [Hazard Ratio (HR): 0.341, 95% Confidence Interval (CI): 0.153-0.759; Wald: 6.945; P = 0.008), whereas it had no influence on motor progression (HR: 0.885, 95% CI: 0.662-1.183; Wald: 0.680; P > 0.10)., Conclusion: Speech difficulties are associated with greater autonomic dysfunction, sleep disturbances and striatal dopaminergic deficit, and can serve as a predictor of faster cognitive decline in early Parkinson's disease., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The ecological management effectiveness (EME) of Marine Protected Areas (MPAs) is the degree to which MPAs reach their ecological goals. The significant variability of EME among MPAs has been partly explained by MPA design, management and implementation features (e.g. surface area, enforcement, age of protection). We investigated EME variability by employing, for the first time, Organization Science. Eight Mediterranean MPAs were taken into account as case studies to explore the relationships between EME and MPA features, such as: 1) organizational size (i.e. the ratio between the number of full-time employees and the total MPA surface area), 2) management performance (i.e. the level of effort exerted to enhance and sustain the MPA management, including enforcement), 3) total surface area, and 4) MPA age. The log-response ratios of fish biomass and density in protected vs unprotected (control) areas were used as a proxy of EME. Management performance, organizational size and, to a lesser extent, MPA age were positively correlated with the log-response ratio of fish biomass, whereas total surface area did not display a significant role. None of the four features considered was significantly correlated with the log-response ratio of fish density. Based on our findings, we argue that the employment of Organization Science in the management effectiveness assessment can assist MPA managers to reach MPAs goals more effectively, with a more efficient use of available resources., (Copyright © 2019. Published by Elsevier Ltd.)

Objectives: To investigate whether baseline [ 123 I]FP-CIT SPECT and CSF markers can predict cognitive impairment (CI) in PD patients, and provide a profile of those most at risk., Methods: 262 de novo PD patients from the Parkinson's Progression Markers Initiative database were stratified into two CI groups at the 36-month follow-up: MoCA-defined diagnosis: PD patients who had a MoCA score < 26; neuropsychological test-defined diagnosis: PD patients with MoCA-defined diagnosis and at least two test scores (of six; irrespective of test domain) greater than 1.5 standard deviation below the mean score in healthy controls. Predictive variables of CI were divided into deciles, providing us with ideal cutoff values for each variable., Results: At the 36-month follow-up, 108/262 (41.2%) PD patients had CI as defined by the MoCA, of which 40/108 (37.0%) had neuropsychological test-defined CI. Baseline CSF Aβ42 (hazard ratio [HR]: 0.996, confidence interval [CI]: 0.992-0.999, p = 0.025), CSF total tau ([HR]: 1.023, [CI]: 1.002-1.044, p = 0.031) and caudate [ 123 I]FP-CIT SPECT uptake ([HR]: 0.332, [CI]: 0.115-0.960, p = 0.042) were predictors of CI. Patients with reduced CSF Aβ42 (< 384.6 pg/mL), increased CSF total tau (> 45.0 pg/mL) and reduced caudate [ 123 I]FP-CIT SPECT uptake (< 1.82) had a 65% risk of developing CI at 36-month follow-up., Conclusion: We report a characteristic profile (reduced CSF Aβ42, increased CSF total tau and reduced caudate [ 123 I]FP-CIT SPECT uptake) that enables identification of early PD patients at risk of developing CI. These findings confirm previous reports of low CSF Aβ42, elevated CSF total tau and reduced dopaminergic integrity being associated with cognitive decline in PD.

Background: Imaging studies have revealed cortical thinning and subcortical atrophy occurring in Parkinson's disease (PD); however, the topographical distribution and clinical associations related to advancing stages of PD remains unclear., Objective: We aimed to investigate the topographical distribution of cortical and subcortical morphometric changes, and their clinical associations, related to increasing disease severity., Methods: In this cross-sectional imaging study, T1-weighted structural magnetic resonance imaging data for 80 non-demented PD patients and 30 age-matched healthy controls were analysed using FreeSurfer software suite to derive morphometric changes using whole-brain vertex-wise analysis, and surface-based (cortical) and volume-based (subcortical) parcellation maps. PD patients were divided into three groups of mild (n = 27), moderate (n = 27), and severe (n = 26) PD based disease duration and Hoehn and Yahr and Unified Parkinson's Disease Rating Scale Part-III motor severity scores., Results: Whole-brain vertex-wise analysis revealed cortical thinning in the orbitofrontal cortex in early PD (P = .011), and in the superior frontal (P = .002), caudal middle frontal gyrus (P = .001) and inferior parietal cortex (P = .006) in moderate PD. Severe PD patients showed additional cortical thinning in temporal and occipital cortices (P < .005). Subcortical volume loss was detected in the thalamus (P = .012) and hippocampus (P = .032) in moderate PD, which extended to the caudate (P = .012), putamen (P = .042) and amygdala (P = .008) in severe PD. Increasing disease duration and motor severity scores, correlated with cortical thinning in frontal, temporal, parietal and occipital cortices, and subcortical volumetric loss in the thalamus, caudate, putamen, amygdala and hippocampus. Lower global cognitive status, measured with MMSE, correlated with cortical thinning in temporal, parietal, frontal and cingulate cortices, and with volumetric loss in the hippocampus (r = 0.31; P = .009); suggesting subclinical pathogenic changes occur prior to the onset of cognitive impairment., Conclusion: In conclusion, in more severe disease stages PD patients exhibit progressive cortical thinning and subcortical volume loss which could have relevance to the development of cognitive impairment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Flexible bronchoscopes are heat labile, complex and difficult to clean, and some nosocomial outbreaks related to bronchoscopy have been reported in literature. The aim of our study was to determine, through a systematic monitoring, whether bronchoscopes' cleaning and disinfection procedures have been correctly adopted by health operators., Methods: We conducted a 19 months-long prospective study in the Unit of Pulmonology at Careggi Teaching Hospital (Florence, Italy), analyzing endoscopes that were reprocessed through a high-level disinfection procedure. Samples collection was performed weekly by two trained operators. Results were organized in a database and then exported for descriptive and inferential statistical analysis., Results: From February 2016 to September 2017 we collected 218 samples from bronchoscopes' valves (N=109) and from their inner channels (N=109). Staphylococci were found in 34 samples (15.69% of all samples). Pseudomonas was found in 11 samples (5.04% of all samples). Pseudomonas aeruginosa wasn't found in any sample., Conclusions: Our results came out to be better than similar studies in literature and demonstrated that a correct endoscopes' hygiene should be part of a more complex strategy of surveillance and control of healthcare-associated infections. However, a continuous monitoring of endoscopes could provide a wider view about this problem, and more reliable results.

Purpose: To assess disease-related patterns of in vivo pathology in 11 patients with Corticobasal Syndrome (CBS) compared to 20 healthy controls and 33 mild cognitive impairment (MCI) patients due to Alzheimer's disease., Methods: We assessed tau aggregates with [ 18 F]AV1451 PET, amyloid-β depositions with [ 18 F]AV45 PET, and volumetric microstructural changes with MRI. We validated for [ 18 F]AV1451 standardised uptake value ratio (SUVRs) against input functions from arterial metabolites and found that SUVRs and arterial-derived distribution volume ratio (DVRs) provide equally robust measures of [ 18 F]AV1451 binding., Results: CBS patients showed increases in [ 18 F]AV1451 SUVRs in parietal (P < 0.05) and frontal (P < 0.05) cortices in the affected hemisphere compared to healthy controls and in precentral (P = 0.008) and postcentral (P = 0.034) gyrus in the affected hemisphere compared to MCI patients. Our data were confirmed at the histopathological level in one CBS patient who underwent brain biopsy and showed sparse tau pathology in the parietal cortex co-localizing with increased [ 18 F]AV1451 signal. Cortical and subcortical [ 18 F]AV45 uptake was within normal levels in CBS patients. In parietal and frontal cortices of the most affected hemisphere we found also grey matter loss (P < 0.05), increased mean diffusivity (P < 0.05) and decreased fractional anisotropy (P < 0.05) in CBS patients compared to healthy controls and MCI patients. Grey matter loss and white matter changes in the precentral gyrus of CBS patients were associated with worse motor symptoms., Conclusions: Our findings demonstrate disease-related patterns of in vivo tau and microstructural pathology in the absence of amyloid-β, which distinguish CBS from non-affected individuals and MCI patients.

Background: Striatal cyclic adenosine monophosphate activity modulates movement and is determined from the balance between its synthesis by adenylate cyclase 5 (ADCY5) and its degradation by phosphodiesterase 10A (PDE10A)., Objective: We assessed the integrity of striatocortical pathways, in vivo, in 2 genetic hyperkinetic disorders caused by ADCY5 and PDE10A mutations., Methods: We studied 6 subjects with PDE10A and ADCY5 mutations using [ 11 C]IMA107 PET, [ 123 I]FP-CIT Single-photon emission computed tomography (SPECT) and multimodal MRI to investigate PDE10A and dopamine transporter availability, neuromelanin-containing neurons, and microstructural white and gray matter changes, respectively., Results: We found that PDE10A and ADCY5 mutations were associated with decreased PDE10A expression in the striatum and globus pallidus, decreased dopamine transporter expression in the striatum, loss of substantia nigra neuromelanin-containing neurons, and microstructural white and gray matter changes within the substantia nigra, striatum, thalamus, and frontoparietal cortices., Conclusions: Our findings indicate an association between PDE10A and ADCY5 mutations and pre/postsynaptic molecular changes, substantia nigra damage, and white and gray matter changes within the striatocortical pathways. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

In August 2018 a Moroccan man living in Tuscany developed Plasmodium falciparum malaria. The patient declared having not recently visited any endemic country, leading to diagnostic delay and severe malaria. As susceptibility to P. falciparum of Anopheles species in Tuscany is very low, and other risk factors for acquiring malaria could not be completely excluded, the case remains cryptic, similar to other P. falciparum malaria cases previously reported in African individuals living in Apulia in 2017.

Marine Protected Areas (MPAs) are important tools to achieve marine conservation and resources management goals. The management effectiveness of MPAs (the degree to which MPAs achieve their goals) is highly variable and can be affected by many MPA attributes, for example their design, enforcement and age. Another key factor possibly affecting MPA management effectiveness is the management performance, here conceived according to Horigue et al. definition (2014) as the "level of effort exerted to enhance and sustain management of MPAs". Organization Science (OS), the discipline that studies organizations, can offer a useful framework to assess and interpret MPA management performance. Using an exploratory multiple case study approach, we applied OS principles to 11 Mediterranean MPAs in order to: i) characterize several MPA organizational features; ii) assess MPA management performance (evaluated as the effort deployed in, for example, planning the future, formalizing measurable goals, and implementing specific strategies). Results show that a number of organizational features and networking attributes are highly variable among the MPAs we have studied. For instance, goals are seldom measurable and the strategy to achieve goals is not systematically pursued. Two relevant outcomes emerge from this exploratory study: i) the management performance of the MPAs considered needs considerable improvements; ii) the methods and the approach proposed could help MPAs' managers and policy makers to understand how to improve their management performance and, consequently, their effectiveness., (Copyright © 2018. Published by Elsevier Ltd.)

Background: A dialyzed patient weekly gets in touch with a large amount of water (on average 350 liters) through the dialysis bath. It is therefore essential that this solution would have a high quality and purity. The aim of our study was to monitor the microbiological quality of the hemodialysis water in order to identify possible factors that could affect it., Methods: We conducted a cross-sectional study from January 2015 to October 2017 collecting the dialysis water in AOU Careggi. Samples were aseptically collected by specialized technicians and then transported under ice at 4° C to the Laboratory of Biological Hazards of USL Toscana Centro for laboratory analyses., Results: 126 water samples were collected. Coliforms, E. coli, Staphylococcus aureus, enterococci were not detected. Pseudomonas aeruginosa was found in only one sample. Both for CFU at 37° C and at 22° C, the type of device represented the only statistically significant risk factor (OR 15.21 and OR 10.25 respectively): SDS devices had a significantly higher risk of being positive for CFU at 37° C and 22° C., Conclusions: As our study demonstrated, the system producing dialysis water must be constantly monitored, especially in cases of SDS devices which may be subjected more frequently to a higher contamination, due to their discontinuous use., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

The purpose of review is to review the current status of positron emission tomography (PET) molecular imaging of serotonergic system in Parkinson's patients who experience levodopa-induced (LIDs) and graft-induced dyskinesias (GIDs). PET imaging studies have shown that Parkinson's disease is characterized by progressive loss of dopaminergic and serotonergic neurons. Parkinson's patients who experienced LIDs and GIDs have an aberrant spreading of serotonergic terminals, which lead to an increased serotonergic/dopaminergic terminals ratio within the putamen. Serotonergic terminals convert exogenous levodopa into dopamine in a non-physiological manner and release an abnormal amount of dopamine without an auto-regulatory feedback. This results in higher swings in synaptic levels of dopamine, which leads to the development of LIDs and GIDs. The modulation of serotonergic terminals with 5-HT 1A and 5-HT 1B receptors agonists partially reduced these motor complications. In vivo PET studies confirmed that abnormal spreading of serotonergic terminals within the putamen has a pivotal role in the development of LIDs and GIDs. However, glutamatergic, adenosinergic, opioid systems, and phosphodiesterases 10A may also play a role in the development of these motor complications. An integrative multimodal imaging approach combining PET and MRI imaging techniques is needed to fully understand the mechanisms underlying the development of LIDs and GIDs.

Objective: To investigate whether diabetes mellitus is associated with Parkinson-like pathology in people without Parkinson disease and to evaluate the effect of diabetes mellitus on markers of Parkinson pathology and clinical progression in drug-naive patients with early-stage Parkinson disease., Methods: We compared 25 patients with Parkinson disease and diabetes mellitus to 25 without diabetes mellitus, and 14 patients with diabetes mellitus and no Parkinson disease to 14 healthy controls (people with no diabetes mellitus or Parkinson disease). The clinical diagnosis of diabetes mellitus was confirmed by 2 consecutive fasting measurements of serum glucose levels >126 mL/dL. Over a 36-month follow-up period, we then investigated in the population with Parkinson disease whether the presence of diabetes mellitus was associated with faster motor progression or cognitive decline., Results: The presence of diabetes mellitus was associated with higher motor scores ( p < 0.01), lower striatal dopamine transporter binding ( p < 0.05), and higher tau CSF levels ( p < 0.05) in patients with Parkinson disease. In patients with diabetes but without Parkinson disease, the presence of diabetes mellitus was associated with lower striatal dopamine transporter binding ( p < 0.05) and higher tau ( p < 0.05) and α-synuclein ( p < 0.05) CSF levels compared to healthy controls. At the Cox survival analysis in the population of patients with Parkinson disease, the presence of diabetes mellitus was associated with faster motor progression (hazard ratio = 4.521, 95% confidence interval = 1.468-13.926; p < 0.01) and cognitive decline (hazard ratio = 9.314, 95% confidence interval = 1.164-74.519; p < 0.05)., Conclusions: Diabetes mellitus may predispose toward a Parkinson-like pathology, and when present in patients with Parkinson disease, can induce a more aggressive phenotype., (© 2018 American Academy of Neurology.)

Excessive daytime sleepiness (EDS) is one of the earliest and most common non-motor symptoms of PD, substantially impacting on patient's quality of life. Using the Parkinson's Progression Markers Initiative database, we performed a case-control study to investigate whether dopaminergic deficit is associated with the development of EDS using dopaminergic specific single photon emission computed tomography (SPECT) molecular imaging of dopamine transporters (DAT). We enrolled 84 early de novo PD patients with EDS and 84 without EDS, who were matched for age, gender, age of diagnosis, years of education and disease duration. We assessed and compared semi-quantified [ 123 I]FP-CIT SPECT, and motor and non-motor features among these two groups, alongside exploring the clinical and imaging correlates of EDS and the predictive significance of these markers in the development of EDS. PD patients with EDS had worse non-motor (MDS-UPDRS Part-I, P < 0.001) and motor (MDS-UPRDS Part-II, P = 0.005) experiences of daily living, as well as worse autonomic (SCOPA-AUT, P < 0.0001) and cognitive (MoCA P = 0.05) function, depression (GDS, P = 0.002), and reduced caudate DAT ([ 123 I]FP-CIT, P = 0.024) compared to PD patients without EDS. Lower caudate [ 123 I]FP-CIT values correlated with higher EDS scores (r = -0.192, P = 0.013). Among patients without EDS, 47 PD patients (56%) developed EDS over a median follow-up of 36 months. Cox multivariate analysis, including all clinical and imaging data available, revealed that abnormal caudate [ 123 I]FP-CIT uptake (P = 0.030) and disease duration (P = 0.018) were predictors for the development of EDS. Although our findings indicate that dopaminergic deficits in the caudate may be associated to EDS in patients with PD, the pathophysiological causality is debateable, given that dopamine caudate denervation may covary with dopaminergic involvement at other targets and with non-dopaminergic involvement., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives/background: Excessive daytime sleepiness (EDS) is a common disorder, which can manifest in isolation or in combination with other neurological or psychiatric disorders. We know relatively little about the mechanisms underlying the development of EDS and the clinical management of patients with EDS remains an unmet need. In this study, we hypothesised that thalamic dopaminergic function would be altered in subjects with EDS and we sought to investigate this by assessing [ 123 I]FP-CIT Single Photon Emission Computed Tomography (SPECT) data, which is a molecular imaging marker of dopamine transporter (DAT)., Patients/methods: We performed a case-control study using people registered as healthy subjects in the Parkinson's Progression Markers Initiative database. We assessed and compared semi-quantified [ 123 I]FP-CIT-SPECT in two groups of 21 healthy subjects with and without EDS, who were matched for age, gender, years of education and Rapid eyemovement (REM) sleep behaviour disorder (RBD) Questionnaire scores., Results: Our findings show increased thalamic DAT binding in people with EDS compared to matched healthy subjects without EDS. Higher thalamic DAT binding also correlated with worse EDS scores., Conclusion: Our findings provide evidence that increased dopaminergic function in the thalamus may mediate excessive daytime sleepiness in humans., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Over the past years, positron emission tomography (PET) imaging studies have investigated striatal molecular changes in premanifest and manifest Huntington's disease (HD) gene expansion carriers (HDGECs), but they have yielded inconsistent results., Objective: To systematically examine the evidence of striatal molecular alterations in manifest and premanifest HDGECs as measured by PET imaging studies., Methods: MEDLINE, ISI Web of Science, Cochrane Library and Scopus databases were searched for articles published until 7 June 2017 that included PET studies in manifest and premanifest HDGECs. Meta-analyses were conducted with random effect models, and heterogeneity was addressed with I 2 index, controlling for publication bias and quality of study. The primary outcome was the standardised mean difference (SMD) of PET uptakes in the whole striatum, caudate and putamen in manifest and premanifest HDGECs compared with healthy controls (HCs)., Results: Twenty-four out of 63 PET studies in premanifest (n=158) and manifest (n=191) HDGECs and HCs (n=333) were included in the meta-analysis. Premanifest and manifest HDGECs showed significant decreases in dopamine D 2 receptors in caudate (SMD=-1.233, 95% CI -1.753 to -0.713, p<0.0001; SMD=-5.792, 95% CI -7.695 to -3.890, p<0.0001) and putamen (SMD=-1.479, 95% CI -1.965 to -0.992, p<0.0001; SMD=-5.053, 95% CI -6.558 to -3.549, p<0.0001), in glucose metabolism in caudate (SMD=-0.758, 95% CI -1.139 to -0.376, p<0.0001; SMD=-3.738, 95% CI -4.880 to -2.597, p<0.0001) and putamen (SMD=-2.462, 95% CI -4.208 to -0.717, p=0.006; SMD=-1.650, 95% CI -2.842 to -0.458, p<0.001) and in striatal PDE10A binding (SMD=-1.663, 95% CI -2.603 to -0.723, p=0.001; SMD=-2.445, 95% CI -3.371 to -1.519, p<0.001)., Conclusions: PET imaging has the potential to detect striatal molecular changes even at the early premanifest stage of HD, which are relevant to the neuropathological mechanisms underlying the development of the disease., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic nigrostriatal connections which is recognized as the major pathophysiological event underlying the onset of motor symptoms. Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) imaging allow the study of these connections in vivo at a molecular level. Several radiotracers have been developed targeting the synthesis and metabolism of dopamine and dopaminergic receptors to investigate the nigrostriatal pathway in vivo. Molecular imaging has greatly increased our knowledge on the progression and natural history of PD, as well as the development of motor and non-motor symptoms. PET molecular imaging could be a reliable biomarker to aid earlier diagnosis and for monitoring disease progression. Furthermore, PET imaging could be used as outcome measure in the design of clinical trials testing novel pharmacological compounds aiming to slow, and ultimately halt, disease progression., (© 2018 Elsevier Inc. All rights reserved.)

Objective: To assess in vivo the expression of phosphodiesterase 4 (PDE4) and its relevance to cognitive symptoms in patients with Parkinson disease (PD) using [ 11 C]rolipram PET., Methods: We studied 12 levodopa-treated patients with PD with no concurrent diagnosis of mild cognitive impairment or dementia. Their data were compared with those from 12 healthy controls. All participants underwent neuropsychiatric and cognitive assessment using the Cambridge Neuropsychological Test Automated Battery. Parametric images of [ 11 C]rolipram volume of distribution (V T ) values were determined with the Logan plot., Results: Patients with PD performed worse than healthy controls in cognitive examinations assessing psychomotor speed, episodic memory, and spatial working memory and executive function. Patients with PD showed reductions in [ 11 C]rolipram V T compared to healthy controls, in the caudate (28%), thalamus (23%), hypothalamus (32%), and cortex (16%). Within thalamic subregions, [ 11 C]rolipram V T values in patients with PD were decreased by 12%-32%, with most marked decreases observed in prefrontal and temporal thalamic nuclei, whereas motor nuclei were less affected. Within the cortex, [ 11 C]rolipram V T values in patients with PD were decreased by 11%-20%, with most marked decreases observed in posterior dorsolateral frontal cortex, medial frontal cortex, and supplementary motor area, whereas orbitofrontal cortex was less affected. Worse performance in spatial working memory correlated with lower [ 11 C]rolipram V T values in posterior dorsolateral frontal cortex, medial frontal cortex, supplementary motor area, precentral gyrus, caudate, and prefrontal thalamic nuclei., Conclusions: Our findings demonstrate loss of PDE4 expression in the striato-thalamo-cortical circuit, which is associated with deficits of spatial working memory in patients with PD., (© 2017 American Academy of Neurology.)

In this study, we investigate the application of multi-parametric anato-functional (MR-PET) priors for the maximum a posteriori (MAP) reconstruction of brain PET data in order to address the limitations of the conventional anatomical priors in the presence of PET-MR mismatches. In addition to partial volume correction benefits, the suitability of these priors for reconstruction of low-count PET data is also introduced and demonstrated, comparing to standard maximum-likelihood (ML) reconstruction of high-count data. The conventional local Tikhonov and total variation (TV) priors and current state-of-the-art anatomical priors including the Kaipio, non-local Tikhonov prior with Bowsher and Gaussian similarity kernels are investigated and presented in a unified framework. The Gaussian kernels are calculated using both voxel- and patch-based feature vectors. To cope with PET and MR mismatches, the Bowsher and Gaussian priors are extended to multi-parametric priors. In addition, we propose a modified joint Burg entropy prior that by definition exploits all parametric information in the MAP reconstruction of PET data. The performance of the priors was extensively evaluated using 3D simulations and two clinical brain datasets of [ 18 F]florbetaben and [ 18 F]FDG radiotracers. For simulations, several anato-functional mismatches were intentionally introduced between the PET and MR images, and furthermore, for the FDG clinical dataset, two PET-unique active tumours were embedded in the PET data. Our simulation results showed that the joint Burg entropy prior far outperformed the conventional anatomical priors in terms of preserving PET unique lesions, while still reconstructing functional boundaries with corresponding MR boundaries. In addition, the multi-parametric extension of the Gaussian and Bowsher priors led to enhanced preservation of edge and PET unique features and also an improved bias-variance performance. In agreement with the simulation results, the clinical results also showed that the Gaussian prior with voxel-based feature vectors, the Bowsher and the joint Burg entropy priors were the best performing priors. However, for the FDG dataset with simulated tumours, the TV and proposed priors were capable of preserving the PET-unique tumours. Finally, an important outcome was the demonstration that the MAP reconstruction of a low-count FDG PET dataset using the proposed joint entropy prior can lead to comparable image quality to a conventional ML reconstruction with up to 5 times more counts. In conclusion, multi-parametric anato-functional priors provide a solution to address the pitfalls of the conventional priors and are therefore likely to increase the diagnostic confidence in MR-guided PET image reconstructions.

It is estimated that up to 80% of patients with Parkinson's disease will eventually develop cognitive impairment over the course of their illness. Even at the time of diagnosis, cognitive impairment has been reported in 20-25% of patients. Commonly affected cognitive domains are executive function, visuospatial ability and attention control. In addition, patients with Parkinson's disease dementia may present with deficits in language function and verbal memory. Psychosis may occur in approximately 40% of patients with Parkinson's disease, and is associated with an increased risk of developing cognitive impairment. Studies have shown that patients with Parkinson's disease with a history of visual hallucinations had an increased risk of developing dementia, four to eight years following diagnosis of the disease. Other clinical risk factors associated with cognitive decline in patients with Parkinson's disease include older age of onset, severe motor symptom burden and in particular akinetic-rigid subtype and olfactory dysfunction. Patients with Parkinson's disease who present with symptoms of cognitive decline, behavioural changes or psychotic symptoms should be referred for further investigation.

Positron emission tomography (PET) is a powerful analytical tool for in vivo molecular imaging of the human brain. Over the past years, a number of PET studies imaging the serotonin transporter (SERT) have been used and provided evidence for the key role of serotonergic pathology in patients with Parkinson's disease (PD). Here, we review the role of SERT in the development of motor and nonmotor complications in patients with PD, and we performed a meta-analysis to identify the patterns of SERT pathology and the relevance to symptoms. Consistent SERT pathology in raphe nuclei, striatum, thalamus, and hypothalamus and associations with aging, PD progression, development of dyskinesias, and cognitive decline were observed. Ann Neurol 2017;81:171-180., (© 2016 American Neurological Association.)

Asplenic or hyposplenic (AH) individuals are particularly vulnerable to invasive infections caused by encapsulated bacteria. Such infections have often a sudden onset and a fulminant course. Infectious diseases (IDs) incidence in AH subjects can be reduced by preventive measures such as vaccination. The aim of our work is to provide updated recommendations on prevention of infectious diseases in AH adult patients, and to supply a useful and practical tool to healthcare workers for the management of these subjects, in hospital setting and in outpatients consultation. A systematic literature review on evidence based measures for the prevention of IDs in adult AH patients was performed in 2015. Updated recommendations on available vaccines were consequently provided. Vaccinations against S. pneumoniae, N. meningitidis, H. influenzae type b and influenza virus are strongly recommended and should be administered at least 2 weeks before surgery in elective cases or at least 2 weeks after the surgical intervention in emergency cases. In subjects without evidence of immunity, 2 doses of live attenuated vaccines against measles-mumps-rubella and varicella should be administered 4-8 weeks apart from each other; a booster dose of tetanus, diphtheria and pertussis vaccine should be administered also to subjects fully vaccinated, and a 3-dose primary vaccination series is recommended in AH subjects with unknown or incomplete vaccination series (as in healthy people). Evidence based prevention data support the above recommendations to reduce the risk of infection in AH individuals.

Huntington's disease (HD) is a progressive, monogenic dominant neurodegenerative disorder caused by repeat expansion mutation in the huntingtin gene. The accumulation of mutant huntingtin protein, forming intranuclear inclusions, subsequently leads to degeneration of medium spiny neurons in the striatum and cortical areas. Genetic testing can identify HD gene carriers before individuals develop overt cognitive, psychiatric, and chorea symptoms. Thus, HD gene carriers can be studied in premanifest stages to understand and track the evolution of HD pathology. While advances have been made, the precise pathophysiological mechanisms underlying HD are unclear. Magnetic resonance imaging (MRI) and positron emission tomography (PET) have been employed to understand HD pathology in presymptomatic and symptomatic disease stages. PET imaging uses radioactive tracers to detect specific changes, at a molecular level, which could be used as markers of HD progression and to monitor response to therapeutic treatments for HD gene expansion carriers (HDGECs). This review focuses on available PET techniques, employed in cross-sectional and longitudinal human studies, as biomarkers for HD, and highlights future potential PET targets. PET studies have assessed changes in postsynaptic dopaminergic receptors, brain metabolism, microglial activation, and recently phosphodiesterase 10A (PDE10A) as markers to track HD progression. Alterations in PDE10A expression are the earliest biochemical change identified in HD gene carriers up to 43 years before predicted symptomatic onset. Thus, PDE10A expression could be a promising marker to track HD progression from early premanifest disease stages. Other PET targets which have been less well investigated as biomarkers include cannabinoid, adenosine, and GABA receptors. Future longitudinal studies are required to fully validate these PET biomarkers for use to track disease progression from far-onset premanifest to manifest HD stages. PET imaging is a crucial neuroimaging tool, with the potential to detect early changes and validate sensitivity of biomarkers for tracking HD pathology. Moreover, continued development of novel PET tracers provides exciting opportunities to investigate new molecular targets, such as histamine and serotonin receptors, to further understand the mechanisms underlying HD pathology.

Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by the loss of nigrostriatal dopaminergic neurons and aggregation of misfolded α-synuclein in Lewy bodies. The underlying mechanisms of neurodegeneration in PD are still unknown, and there are no disease-modifying treatments to slow the neurodegenerative processes. There is an urgent need to identify biomarkers that are able to monitor disease progression and assess the development and efficacy of novel disease-modifying drugs. Over the past years, neuroimaging techniques such as magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), and positron emission tomography (PET) have provided important advances in our understanding of PD. MRI provides information about structural and functional organization of the brain, while SPECT and PET can detect molecular changes in the brain. Here, we review the current neuroimaging literature in sporadic and genetic PD, which have contributed to our understanding of the physiopathological mechanisms of the disease., (© 2017 Elsevier Inc. All rights reserved.)

Purpose: To systematically review the previous studies and current status of positron emission tomography (PET) molecular imaging research in atypical parkinsonism., Methods: MEDLINE, ISI Web of Science, Cochrane Library, and Scopus electronic databases were searched for articles published until 29th March 2016 and included brain PET studies in progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal syndrome (CBS). Only articles published in English and in peer-reviewed journals were included in this review. Case-reports, reviews, and non-human studies were excluded., Results: Seventy-seven PET studies investigating the dopaminergic system, glucose metabolism, microglial activation, hyperphosphorilated tau, opioid receptors, the cholinergic system, and GABA A receptors in PSP, MSA, and CBS patients were included in this review. Disease-specific patterns of reduced glucose metabolism have shown higher accuracy than dopaminergic imaging techniques to distinguish between parkinsonian syndromes. Microglial activation has been found in all forms of atypical parkinsonism and reflects the known distribution of neuropathologic changes in these disorders. Opioid receptors are decreased in the striatum of PSP and MSA patients. Subcortical cholinergic dysfunction was more severe in MSA and PSP than Parkinson's disease patients although no significant changes in cortical cholinergic receptors were seen in PSP with cognitive impairment. GABA A receptors were decreased in metabolically affected cortical and subcortical regions in PSP patients., Conclusions: PET molecular imaging has provided valuable insight for understanding the mechanisms underlying atypical parkinsonism. Changes at a molecular level occur early in the course of these neurodegenerative diseases and PET imaging provides the means to aid differential diagnosis, monitor disease progression, identify of novel targets for pharmacotherapy, and monitor response to new treatments., Competing Interests: Dr. Marios Politis declares that he has no conflict of interest. Dr. Flavia Niccolini declares that she has no conflict of interest. Ethical approval This article does not contain any studies with human participants performed by any of the authors. Informed consent Informed consent was obtained from all individual participants included in all the study reported in this review.

Huntington's disease (HD) is a monogenic neurodegenerative disorder with an underlying pathology involving the toxic effect of mutant huntingtin protein primarily in striatal and cortical neurons. Phosphodiesterase 10A (PDE10A) regulates intracellular signalling cascades, thus having a key role in promoting neuronal survival. Using positron emission tomography (PET) with [(11)C]IMA107, we investigated the in vivo extra-striatal expression of PDE10A in 12 early premanifest HD gene carriers. Image processing and kinetic modelling was performed using MIAKAT™. Parametric images of [(11)C]IMA107 non-displaceable binding potential (BPND) were generated from the dynamic [(11)C]IMA107 scans using the simplified reference tissue model with the cerebellum as the reference tissue for nonspecific binding. We set a threshold criterion for meaningful quantification of [(11)C]IMA107 BPND at 0.30 in healthy control data; regions meeting this criterion were designated as regions of interest (ROIs). MRI-based volumetric analysis showed no atrophy in ROIs. We found significant differences in mean ROIs [(11)C]IMA107 BPND between HD gene carriers and healthy controls. HD gene carriers had significant loss of PDE10A within the insular cortex and occipital fusiform gyrus compared to healthy controls. Insula and occipital fusiform gyrus are important brain areas for the regulation of cognitive and limbic function that is impaired in HD. Our findings suggest that dysregulation of PDE10A-mediated intracellular signalling could be an early phenomenon in the course of HD with relevance also for extra-striatal brain areas., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The clinical presentation of Parkinson's disease (PD) is heterogeneous and overlaps with other conditions, including the parkinsonian variant of multiple system atrophy (MSA-P), progressive supranuclear palsy (PSP) and essential tremor. Imaging of the brain in patients with parkinsonism has the ability to increase the accuracy of differential diagnosis. Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) allow brain imaging of structural, functional and molecular changes in vivo in patients with PD. Structural MRI is useful to differentiate PD from secondary and atypical forms of parkinsonism. 123I-ioflupane (DaTSCAN(TM)) SPECT is a valid tool in the differential diagnosis between PD and non-degenerative tremors, while cardiac 123I-metaiodobenzylguanidine SPECT and 18F-fluorodeoxyglucose PET are valid in the differential diagnosis between PD and atypical parkinsonism (MSA-P, PSP). However, despite significant evidence for the utility of neuroimaging in assessing parkinsonian patients, none of the neuroimaging techniques are specifically recommended for routine use in clinical practice. Hopefully, future larger trials will help to demonstrate additional evidence for the clinical utility of neuroimaging and will include an analysis of the financial benefits for the NHS in the longer term management of the patients., (© 2016 Royal College of Physicians.)

Objective: Phosphodiesterase 10A (PDE10A) is an enzyme present in striatal medium spiny neurons that degrades the intracellular second messengers triggered by dopamine signaling. The pharmaceutical industry has considerable interest in PDE10A inhibitors because they have been shown to have an antipsychotic-like effect in animal models. However, the status of PDE10A in schizophrenia is unknown. Using a newly developed and validated radioligand, [(11)C]IMA107, the authors report the first in vivo assessment of PDE10A brain expression in patients with schizophrenia., Method: The authors compared PDE10A availability in the brains of 12 patients with chronic schizophrenia and 12 matched healthy comparison subjects using [(11)C]IMA107 positron emission tomography (PET). Regional estimates of the binding potential (BPND) of [(11)C]IMA107 were generated from dynamic PET scans using the simplified reference tissue model with the cerebellum as the reference tissue for nonspecific binding., Results: There was no significant difference in [(11)C]IMA107 BPND between schizophrenia patients and comparison subjects in any of the brain regions studied (thalamus, caudate, putamen, nucleus accumbens, globus pallidus, and substantia nigra). There was also no significant correlation between [(11)C]IMA107 BPND and the severity of psychotic symptoms or antipsychotic dosage., Conclusions: Patients with schizophrenia have normal availability of PDE10A in brain regions thought to be involved in the pathophysiology of this disorder. The findings do not support the proposal of an altered PDE10A availability in schizophrenia. The implication of this finding for future drug development is discussed.

The multifaceted nature of the pathology of dementia spectrum disorders has complicated their management and the development of effective treatments. This is despite the fact that they are far from uncommon, with Alzheimer's disease (AD) alone affecting 35 million people worldwide. The cholinergic system has been found to be crucially involved in cognitive function, with cholinergic dysfunction playing a pivotal role in the pathophysiology of dementia. The use of molecular imaging such as SPECT and PET for tagging targets within the cholinergic system has shown promise for elucidating key aspects of underlying pathology in dementia spectrum disorders, including AD or parkinsonian dementias. SPECT and PET studies using selective radioligands for cholinergic markers, such as [(11)C]MP4A and [(11)C]PMP PET for acetylcholinesterase (AChE), [(123)I]5IA SPECT for the α4β2 nicotinic acetylcholine receptor and [(123)I]IBVM SPECT for the vesicular acetylcholine transporter, have been developed in an attempt to clarify those aspects of the diseases that remain unclear. This has led to a variety of findings, such as cortical AChE being significantly reduced in Parkinson's disease (PD), PD with dementia (PDD) and AD, as well as correlating with certain aspects of cognitive function such as attention and working memory. Thalamic AChE is significantly reduced in progressive supranuclear palsy (PSP) and multiple system atrophy, whilst it is not affected in PD. Some of these findings have brought about suggestions for the improvement of clinical practice, such as the use of a thalamic/cortical AChE ratio to differentiate between PD and PSP, two diseases that could overlap in terms of initial clinical presentation. Here, we review the findings from molecular imaging studies that have investigated the role of the cholinergic system in dementia spectrum disorders.

Purpose: To review the developments of recent decades and the current status of PET molecular imaging in Huntington's disease (HD)., Methods: A systematic review of PET studies in HD was performed. The MEDLINE, Web of Science, Cochrane and Scopus databases were searched for articles in all languages published up to 19 August 2015 using the major medical subject heading "Huntington Disease" combined with text and key words "Huntington Disease", "Neuroimaging" and "PET". Only peer-reviewed, primary research studies in HD patients and premanifest HD carriers, and studies in which clinical features were described in association with PET neuroimaging results, were included in this review. Reviews, case reports and nonhuman studies were excluded., Results: A total of 54 PET studies were identified and analysed in this review. Brain metabolism ([(18)F]FDG and [(15)O]H2O), presynaptic ([(18)F]fluorodopa, [(11)C]β-CIT and [(11)C]DTBZ) and postsynaptic ([(11)C]SCH22390, [(11)C]FLB457 and [(11)C]raclopride) dopaminergic function, phosphodiesterases ([(18)F]JNJ42259152, [(18)F]MNI-659 and [(11)C]IMA107), and adenosine ([(18)F]CPFPX), cannabinoid ([(18)F]MK-9470), opioid ([(11)C]diprenorphine) and GABA ([(11)C]flumazenil) receptors were evaluated as potential biomarkers for monitoring disease progression and for assessing the development and efficacy of novel disease-modifying drugs in premanifest HD carriers and HD patients. PET studies evaluating brain restoration and neuroprotection were also identified and described in detail., Conclusion: Brain metabolism, postsynaptic dopaminergic function and phosphodiesterase 10A levels were proven to be powerful in assessing disease progression. However, no single technique may be currently considered an optimal biomarker and an integrative multimodal imaging approach combining different techniques should be developed for monitoring potential neuroprotective and preventive treatment in HD.