Predictors of normal and abnormal outcome in clinical brain dopamine transporter imaging

Brain dopamine transporter (DAT) imaging with [123I]FP-CIT SPECT can be used to evaluate the integrity of the mesostriatal dopaminergic system in patients with clinically uncertain parkinsonism. To evaluate whether scanning a patient is clinically necessary, it is vital to understand possible factors that affect the scanning result. Therefore, we investigated an unselected sample of 538 consecutively scanned patients from a 6-year period, and the demographic data and indications for DAT SPECT were recorded. After scanning, the patients were divided into groups according to the scanning outcome. Multivariate binary logistic regression analyses were performed to investigate whether the pre-imaging variables had independent associations with the outcome of the scan. Three hundred and three (56.3 %) patients had abnormal scans showing a dopaminergic deficit. The independent factors associated with abnormal scans were older age (p = 0.002), asymmetry of motor symptoms (p = 0.005) and shorter symptom duration (p p = 0.004), whereas the possibility of medication-induced parkinsonism was associated with a higher probability of a normal scan (35.4 %, p = 0.036). The probability of an abnormal outcome in clinical brain DAT imaging increases with known risk factors of neurodegenerative parkinsonism. However, a long duration of uncertain motor symptoms and suspicion of medication-induced parkinsonism are associated with a higher probability of a normal outcome. The findings reflect epidemiological factors in parkinsonism together with referral biases that may be used to improve the clinical use of DAT imaging.</p

Survival in Parkinson's disease in relation to striatal dopamine transporter binding

Objective: To investigate whether dopamine transporter (DAT) binding, as measured with single photon emission computed tomography (SPECT), can be used to predict mortality in patients with Parkinson's disease (PD). Methods: A total of 162 patients with PD and abnormal [I-123]FP-CIT SPECT were clinically followed for a median of 5.8 years. A multivariate Cox regression model was used to investigate survival with the independent predictors of age, gender, severity of motor impairment, levodopa-equivalent daily dose of medication, presence of cognitive defects, and putaminal specific binding ratio (SBR) of [I-123]FP-CIT. In addition, associations between striatal and extrastriatal SBRs and survival were investigated using voxel-based analyses.Results: The overall mortality was 25.9%, and the Kaplan-Meier estimate for mortality was 36%. Older age (P< 0.001), presence of cognitive defects (P = 0.001), and more severe motor symptom severity (P = 0.002) were significantly associated with increased mortality. No associations were found between putaminal DAT binding and survival (P = 0.99). There were no significant differences in SBRs in any striatal or extrastriatal region between survivors and non-survivors, and no associations were found between SBRs and scan-to-death intervals among non-survivors.Conclusions: Unlike the severity of motor and cognitive symptoms, the level of striatal dopaminergic defect in DAT SPECT does not predict mortality in PD. Although presynaptic dopaminergic functional imaging may have value as a diagnostic tool, the clinical symptom-based characteristics are superior for predicting lifespan. (c) 2017 Elsevier Ltd. All rights reserved

Ventral striatal dopaminergic defect is associated with hallucinations in Parkinson's disease

ConclusionsLow striatal DAT function may predispose PD patients to VHs, and the regional distribution of the findings suggests a particular role of the ventral striatum. This is in line with non-PD research that has implicated ventral striatal dysfunction in psychosis.</p

Visual versus automated analysis of [I-123]FP-CIT SPECT scans in parkinsonism

The clinical evaluation of dopamine transporter (DAT) SPECT scans typically relies on visual analysis in combination with an automated semi-quantitative method. The interpretation of the results may be difficult in cases that show disagreement between the two methods on the borderline of abnormality. The frequency and clinical characteristics of such cases are unclear. Automated semi-quantitative analyses and independent visual analyses by two experienced nuclear medicine physicians and four inexperienced raters were performed for 120 patients with clinically uncertain parkinsonism scanned with brain [I-123]FP-CIT SPECT. Agreement was evaluated with kappa statistics. The clinical characteristics of patients who had discrepant findings between the two analysis methods were investigated. The expert raters outperformed nonexperts in terms of agreement between visual and automated analyses (kappa = 0.66, 0.72 vs. 0.23-0.54) and between raters (kappa = 0.81 vs. 0.44-0.63). Twelve patients showed discrepant findings between the visual and automated analyses. These patients were older compared to other patients (p = 0.023), had 17.6 % lower mean striatal tracer binding compared to normal scans (p = 0.003) and 62.7 % higher compared to abnormal scans (p < 0.001). After a minimum of 4.5 years of clinical follow-up, none of these patients developed neurodegenerative parkinsonism. Clinical DAT SPECT scans show discrepancies between visual and automated analyses in 10 % of cases. The patients with discrepant findings are older, show normal to slightly abnormal tracer binding, and importantly, do not develop neurodegenerative parkinsonism syndromes. Visual analyses by experienced raters are reliable, but the diagnostic accuracy in discrepant cases can be improved by an automated method

Sex-Dependent Improvement in Survival of Parkinson's Disease Patients

Background Advances in the treatment of Parkinson's disease (PD) and changes in general life expectancy may have improved survival in patients with PD.Objective The objective of this study was to investigate recent trends in PD mortality.Methods In total, 1521 patients with PD in local and national registries were followed for 11 years (2006-2016) from diagnosis until exit date or death, and the causes of death were recorded.Results The survival of men with PD improved during the follow-up period, but no change was observed in women (2-year postdiagnosis survival in men, 79.0%-86.3%, P = 0.03; 2-year postdiagnosis survival in women, 82.8%-87.5%, P = 0.42). Pneumonia was the most common immediate cause of death.Discussion The survival of men with PD has improved in Finland without a similar change in women. Because changes in treatment likely affect both sexes similarly, the results may reflect the decreasing sex gap in life expectancy. This phenomenon will likely increase the already high male-to-female prevalence ratio of PD

Obscuration beyond the nucleus: infrared quasars can be buried in extreme compact starbursts

In the standard quasar model, the accretion disk obscuration is due to the canonical dusty torus. Here, we argue that a substantial part of the quasar obscuration can come from the interstellar medium (ISM) when the quasars are embedded in compact starbursts. We use an obscuration-unbiased sample of 578 infrared (IR) quasars at $z\approx 1-3$ and archival ALMA submillimeter host galaxy sizes to investigate the ISM contribution to the quasar obscuration. We calculate SFR and ISM column densities for the IR quasars and a control sample of submillimeter galaxies (SMGs) not hosting quasar activity and show that: (1) the quasar obscured fraction is constant up to $\rm SFR\approx 300 \: M_{\odot} \: yr^{-1}$, and then increases towards higher SFR, suggesting that the ISM obscuration plays a significant role in starburst host galaxies, and (2) at $\rm SFR\gtrsim 300 \: M_{\odot} \: yr^{-1}$, the SMGs and IR quasars have similarly compact submillimeter sizes ($R_{\rm e}\approx 0.5-3\rm \: kpc$) and, consequently, the ISM can heavily obscure the quasar, even reaching Compton-thick ($N_{\rm H}>10^{24} \rm \: cm^{-2}$) levels in extreme cases. Based on our results, we infer that $\approx 10-30\%$ of the IR quasars with $\rm SFR\gtrsim 300 \: M_{\odot} \: yr^{-1}$ are obscured solely by the ISM.Comment: Accepted for publication in MNRAS Letter

Symptoms and diagnostic delays in bladder cancer with high risk of recurrence: results from a prospective FinnBladder 9 trial

Purpose: To investigate the symptoms and delays in the clinical pathway of bladder cancer (BC).Methods: This is a substudy of a prospective, randomized, multicenter phase III study (FinnBladder 9, NCT01675219) where the efficacy of photodynamic diagnosis and 6 weekly optimized mitomycin C instillations are studied in pTa bladder cancer with high risk for recurrence. The data of presenting symptoms and critical time points were prospectively collected, and the effect of factors on delays was analyzed.Results: At the time of analysis, 245 patients were randomized. Analysis included 131 patients with primary bladder cancer and their complete data. Sixty-nine percent had smoking history and 67% presented with macroscopic hematuria. Median patient delay (from symptoms to health-care contact) was 7 days. The median general practice delay (from health-care contact to urology referral) was 8 days. Median time from urology referral to cystoscopy was 23 days and from cystoscopy to TUR-BT 21 days. Total time used in the clinical pathway (from symptom to TUR-BT) was 78 days. Current and former smokers had non-significantly shorter patient-related and general practice delays compared to never smokers. TUR-BT delay was significantly shorter in patients with malignant cytology (16 days) compared to patients with benign cytology (21 days, p = 0.03).Conclusions: Patient-derived delay was short and most of the delay occurred in the referral centers. The majority had macroscopic hematuria as the initial symptom. Surprisingly, current and past smokers were more prone to contact the health-care system compared to never smokers.</p

Striatal Pre- and Postsynaptic Profile of Adenosine A2A Receptor Antagonists

Striatal adenosine A2A receptors (A2ARs) are highly expressed in medium spiny neurons (MSNs) of the indirect efferent pathway, where they heteromerize with dopamine D2 receptors (D2Rs). A2ARs are also localized presynaptically in cortico-striatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A1 receptors (A1Rs). It has been hypothesized that postsynaptic A2AR antagonists should be useful in Parkinson's disease, while presynaptic A2AR antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessive-compulsive disorders and drug addiction. The aim or this work was to determine whether selective A2AR antagonists may be subdivided according to a preferential pre- versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre- and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre- and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261) showed no clear preference. Radioligand-binding experiments were performed in cells expressing A2AR-D2R and A1R-A2AR heteromers to determine possible differences in the affinity of these compounds for different A2AR heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A2AR when co-expressed with D2R than with A1R. KW-6002 showed the best relative affinity for A2AR co-expressed with D2R than co-expressed with A1R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre- and postsynaptic profile. On the basis of their preferential pre- versus postsynaptic actions, SCH-442416 and KW-6002 may be used as lead compounds to obtain more effective antidyskinetic and antiparkinsonian compounds, respectively