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Inhibition of intracellular N-acylethanolamine-hydrolyzing acid amidase (NAAA) activity is a promising approach to manage the inflammatory response under disabling conditions. In fact, NAAA inhibition preserves endogenous palmitoylethanolamide (PEA) from degradation, thus increasing and prolonging its anti-inflammatory and analgesic efficacy at the inflamed site. In the present work, we report the identification of a potent, systemically available, novel class of NAAA inhibitors, featuring a pyrazole azabicyclo[3.2.1]octane structural core. After an initial screening campaign, a careful structure–activity relationship study led to the discovery of endo-ethoxymethyl-pyrazinyloxy-8-azabicyclo[3.2.1]octane-pyrazole sulfonamide 50 (ARN19689), which was found to inhibit human NAAA in the low nanomolar range (IC50 = 0.042 μM) with a non-covalent mechanism of action. In light of its favorable biochemical, in vitro and in vivo drug-like profile, sulfonamide 50 could be regarded as a promising pharmacological tool to be further investigated in the field of inflammatory conditions.

McLeod syndrome is a rare X-linked recessive genetic disorder that is caused by mutations of the XK gene. It is one of the core neuroacanthocytosis syndromes. We report the case of a 67-year-old man who presented to Kyungpook National University Hospital in the Republic of Korea with progressive worsening of generalized chorea and dystonia. He had no recognized family history of neurologic illness. A peripheral blood smear showed increased acanthocytes. His serum creatine kinase levels were 894 U/L. A brain MRI showed atrophy of the bilateral striatal nuclei. An F-18 F-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane PET/CT showed moderately decreased dopamine transporter uptake in the putamen and severely decreased uptake in the caudate nucleus. An F-18 fludeoxyglucose PET/CT demonstrated markedly decreased metabolism at the caudate nucleus and the putamen. Whole exome sequencing revealed hemizygous pathogenic mutations of the XK gene (c.856_860delCTCTA;p.Leu286TyrfsTer16). We believe that these findings provide useful information regarding the clinical features of individuals with McLeod syndrome.

Delayed phase 18F-FP-CIT PET (dCIT) can assess the striatal dopamine transporter binding to detect degenerative parkinsonism (DP). Early phase 18F-FP-CIT (eCIT) can assess the regional brain activity for differential diagnosis among parkinsonism similar with 18F-FDG PET. We evaluated the diagnostic performance of dual phase 18F-FP-CIT PET (dual CIT) and 18F-FDG PET compared with clinical diagnosis in 141 subjects [36 with idiopathic Parkinson’s disease (IPD), 77 with multiple system atrophy (MSA), 18 with progressive supranuclear palsy (PSP), and 10 with non-DP)]. Visual assessment of eCIT, dCIT, dual CIT, 18F-FDG and 18F-FDG PET with dCIT was in agreement with the clinical diagnosis in 61.7%, 69.5%, 95.7%, 81.6%, and 97.2% of cases, respectively. ECIT showed about 90% concordance with non-DP and MSA, and 8.3% and 27.8% with IPD and PSP, respectively. DCIT showed ≥ 88% concordance with non-DP, IPD, and PSP, and 49.4% concordance with MSA. Dual CIT showed ≥ 90% concordance in all groups. 18F-FDG PET showed ≥ 90% concordance with non-DP, MSA, and PSP, but only 33.3% concordance with IPD. The combination of 18F-FDG and dCIT yielded ≥ 90% concordance in all groups. Dual CIT may represent a powerful alternative to the combination of 18F-FDG PET and dCIT for differential diagnosis of parkinsonian disorders.

Objectives Despite its use in determining nigrostriatal degeneration, the lack of a consistent interpretation of nigrosome 1 susceptibility map-weighted imaging (SMwI) limits its generalized applicability. To implement and evaluate a diagnostic algorithm based on convolutional neural networks for interpreting nigrosome 1 SMwI for determining nigrostriatal degeneration in idiopathic Parkinson's disease (IPD). Methods In this retrospective study, we enrolled 267 IPD patients and 160 control subjects (125 patients with drug-induced parkinsonism and 35 healthy subjects) at our institute, and 24 IPD patients and 27 control subjects at three other institutes on approval of the local institutional review boards. Dopamine transporter imaging served as the reference standard for the presence or absence of abnormalities of nigrosome 1 on SMwI. Diagnostic performance was compared between visual assessment by an experienced neuroradiologist and the developed deep learning-based diagnostic algorithm in both internal and external datasets using a bootstrapping method with 10000 re-samples by the “pROC” package of R (version 1.16.2). Results The area under the receiver operating characteristics curve (AUC) (95% confidence interval [CI]) per participant by the bootstrap method was not significantly different between visual assessment and the deep learning-based algorithm (internal validation, .9622 [0.8912–1.0000] versus 0.9534 [0.8779-0.9956], P = .1511; external validation, 0.9367 [0.8843-0.9802] versus 0.9208 [0.8634-0.9693], P = .6267), indicative of a comparable performance to visual assessment. Conclusions Our deep learning-based algorithm for assessing abnormalities of nigrosome 1 on SMwI was found to have a comparable performance to that of an experienced neuroradiologist.

ObjectiveTo validate the role of the dopamine transporter (DAT) imaging as a biomarker in multiple system atrophy (MSA), we analyzed the association between spatial patterns of [18F]fluoro-propyl-carbomethoxy-iodophenyl-tropane ([18F]FP-CIT) PET and the clinical characteristics of MSA.MethodsSixty-five patients with MSA who underwent [18F]FP-CIT PET between 2009 and 2018 were retrospectively enrolled. To identify spatial patterns of [18F]FP-CIT PET, principal component (PC) analysis was used and correlated with the clinical presentation.ResultsOf the 65 patients, 42 presented with parkinsonian subtype of MSA, and 23 presented with cerebellar subtype of MSA (mean age 63.7 ± 9.3 years; disease duration, 1.8 ± 1.8 years). Each PC represents a specific pattern of degeneration: PC1 and PC2 were associated with the DAT binding of the entire putamen and the posterior putamen, respectively. PC3 was associated with increased [18F]FP-CIT uptake of the caudate and decreased uptake of the dorsal pons. PC2 was significantly correlated with the presence of parkinsonism (p = 5.34 × 10−5) and a positive levodopa response (p = 0.044), with age as a cofactor. PC3 was correlated with the presence of urinary incontinence (p = 0.036). Onset age was significantly correlated with both PC2 (R = 0.48, p = 5.0 × 10−5) and PC3 (R = −0.39, p = 0.0013).ConclusionsThe spatial pattern of DAT binding can reflect distinct clinical features of MSA and provides insight into the underlying pathophysiology of a broad spectrum of clinical features in MSA.

Immunotherapy has shown great potential in cancer therapeutics but has limitations of the insufficient activation of dendritic cells (DCs) and immune-suppressive microenvironment. To overcome these obstacles, a cascade synergistic immunotherapy nanosystem (denoted as CpG@PDA-FA) was designed to elevate anticancer immune response. The combination nanosystem including a photothermal agent polydopamine (PDA) and immunomodulator CpG oligodeoxynucleotides (CpG ODNs). On the one hand, polydopamine (PDA) acts as a photothermal agent to induce low-temperature PTT. It leads to immunogenic cell death (ICD), a programmed cell death pathway, which can activate DCs and enhance the antitumor immune response of T cells. On the other hand, CpG ODNs further promote maturation and migration of DCs as well as ameliorates the immunosuppression microenvironment of the tumor (TME). This paper focuses on a cancer synergistic treatment of ICD-induced immunotherapy by low-temperature PTT and ameliorates TME by immunomodulator CpG ODNs. We proved that CpG@PDA-FA NPs realized a remarkable synergistic treatment effect compared with respective single PTT or CpG therapy in the maturation of DCs and activation of T cells. In addition, CpG@PDA-FA NPs also reduced myeloid-derived suppressor cells and regulatory T cells to relieve immunosuppression. Hence, CpG@PDA-FA NPs provide a bidirectional immunotherapy strategy for tumor inhibition and highlight the cascade effects of low-temperature PTT and immunotherapy.

ObjectiveTo provide evidence that cardiac I-123-metaiodobenzylguanidine sympathetic innervation imaging (MIBG) scintigraphy differentiates probable mild cognitive impairment with Lewy bodies (MCI-LB) from mild cognitive impairment due to Alzheimer disease (MCI-AD), we scanned patients with MCI and obtained consensus clinical diagnoses of their MCI subtype. We also performed baseline FP-CIT scans to compare the accuracy of MIBG and FP-CIT.MethodsWe conducted a prospective cohort study into the accuracy of cardiac MIBG scintigraphy in the diagnosis of MCI-LB. Follow-up clinical assessment was used to diagnose MCI-AD (no core features of MCI-LB and normal FP-CIT), probable MCI-LB (2 or more core features, or 1 core feature with abnormal FP-CIT), or possible MCI-LB (1 core feature or abnormal FP-CIT). For the comparison between MIBG and FP-CIT, only core clinical features were used for diagnosis.ResultsWe recruited 95 people with mild cognitive impairment. Cardiac MIBG was abnormal in 22/37 probable and 2/15 possible MCI-LB cases and normal in 38/43 MCI-AD cases. The sensitivity in probable MCI-LB was 59% (95% confidence interval [CI], 42%–75%), specificity 88% (75%–96%), and accuracy 75% (64%–84%). The positive likelihood ratio was 5.1 and negative likelihood ratio 0.46. With symptom-only diagnoses, the accuracies were 79% for MIBG (95% CI, 68%–87%) and 76% for FP-CIT (95% CI, 65%–85%).ConclusionsCardiac MIBG appears useful in early disease, with an abnormal scan highly suggestive of MCI-LB. Validation in a multicenter setting is justified.Classification of EvidenceThis study provides Class I evidence that cardiac MIBG distinguishes MCI-LB from MCI-AD.

Ipomoea carnea is a toxic plant found in Brazil and other tropical countries. The plant contains the alkaloids calystegines and swainsonine, which inhibit key cellular enzymes and cause systematic cell death. It is known that swainsonine is excreted in the amniotic fluid of dams exposed to the plant. Thus, the aim of this study was to verify whether the toxic effect of I. carnea on fetuses is due to exclusively the passage of the active principle of the plant through the placenta, or if the placentotoxic effect of swainsonine could collaborate in the adverse effects observed in the fetus. The teratogenic effects of exposure to the toxic principles of I. carnea were evaluated not only using the conventional protocol but also at later stages in the postnatal developmental period. Females were treated, from gestation day (GD) 6 until GD19, with 0.0, 1.0, 3.0 or 7.0 g/kg body weight of I. carnea dry leaves. The plant did not induce changes in reproductive performance or biochemical profile of the dams. Dams that received the highest dose of I. carnea showed cytoplasmic vacuolization in the liver, kidney and placental tissue. I. carnea promoted different lectin binding patterns in different areas of placental tissue. No fetal skeletal or visceral malformations was observed. The postnatal evaluation revealed a lower litter weight and a lower pup body weight one day after birth in the group that received the highest dose of I. carnea. Physical milestones were unaffected by the treatments. Female pups from all experimental groups exhibited a delay in achieving a negative geotaxis response. The results show that the toxic principle of I. carnea produces injury in utero in mothers and fetuses, but these deleterious effects were better demonstrated using postnatal evaluation.

Over a millennia, traditional Chinese medicine (TCM) has been used to treat various diseases in China. In recent years, more and more Chinese materia medica (CMM) have been studied in scientific research projects, applied in clinical practice, and their extracts have even appeared in some health products. However, the toxicity of some CMM is often overlooked, including hepatotoxicity, nephrotoxicity, neurotoxicity, cardiotoxicity, etc. In this review, the toxic components and their toxicological mechanisms of some toxic CMM were listed according to the chemical structure classification of toxic components. Afterwards, the traditional methods (processing and compatibility) and modern methods (structural modification, biotransformation, etc.) of attenuation of CMM were discussed. Since ancient times, it has been said that “fight fire with fire, fight poison with poison,” and toxic CMM are of great significance in the treatment of difficult and severe diseases. The rational application of toxic CMM and their components in clinical practice was also exemplified in this review. While the pharmacological effects of TCMs have been emphasized, the scientific attenuation and rational application of toxic components should be concerned. We hope this review can provide a reference for future related research.

Background: Variations in alertness and attention are common in Lewy body diseases (LBD) and among the core features of dementia with Lewy bodies (DLB). Dopamine transporter SPECT is an accurate biomarker of nigrostriatal degeneration (NSD) in LBD. Objective: The present study investigated performance on a computerized alertness test as a potential measure of attention in patients with NSD compared to patients without NSD. Methods: Thirty-six patients with cognitive impairment plus at least one core feature of DLB referred for [123I]FP-CIT SPECT imaging were prospectively recruited. Performance in a computerized test of intrinsic alertness was compared between patients with and those without NSD as assessed by [123I]FP-CIT SPECT. Results: Reaction times to auditory stimuli (adjusted for age, sex, and education) were significantly longer in patients with NSD compared to those with a normal [123I]FP-CIT SPECT scan (p 50 voxels). Conclusion: Computerized assessment of auditory reaction times is able to detect alertness deficits in patients with NSD and might help to measure alertness deficits in patients with LBD and NSD. Future studies in larger samples are needed to evaluate the diagnostic utility of computerized alertness assessment for the differential diagnosis of LBD.

Introduction To better understand the pathophysiology of isolated head tremor, we investigated somatosensory temporal discrimination threshold (STDT) and dopaminergic neurotransmission with 123I-FP-CIT (DAT-SPECT) in patients with isolated head tremor, as well as potential correlations with their clinical features. Methods We enrolled 14 patients with isolated head tremor who underwent clinical examination, STDT testing, and DAT-SPECT. Results We found normal radiotracer uptake in both striata as assessed with DAT-SPECT examination, but higher STDT values in patients as compared to healthy subjects. No significant correlations emerged between STDT values, specific binding ratios of radiotracer uptake, and demographic or clinical features. Conclusion Our study found normal radiotracer uptake with DAT-SPECT examination, suggesting dopaminergic neurotransmission integrity in patients with isolated head tremor. Patients with isolated head tremor exhibited an abnormally elevated STDT. Both results support the hypothesis that isolated head tremor should be considered a form of dystonia.

The aim of this study was to assess the utility of presynaptic dopaminergic imaging using 99mTc-TRODAT-1 SPECT/CT and 18F-FDOPA PET/CT and compare their performance in Parkinson's disease (PD), Parkinson-plus syndrome (PPS), and essential tremor (ET).A total of 103 patients (PD = 48, PPS = 19, and ET = 36) were enrolled prospectively. Hoehn and Yahr (HY) staging and MDS-UPDRS (Movement Disorder Society-Sponsored Revision of Unified Parkinson's Disease Rating Scale) were done for PD and PPS cases. All the patients underwent 99mTc-TRODAT-1 SPECT/CT and 18F-FDOPA PET/CT brain scan. The scans were analyzed visually and semiquantitatively. Average pixel count and SUVmean of the striatum were calculated in SPECT and PET images, respectively, to calculate the specific uptake ratio of striatum (SUR). Comparison of scan findings and SURs among different groups and correlation with clinical characteristics was done.Symmetrical comma-shaped uptake was seen in bilateral striatum in ET cases with mean SURs significantly higher than in cases of early PD (HY stage I and II, n = 37), PD and PPS both on SPECT and PET images (P ≤ 0.001). The mean SURs between PD and PPS showed no significant difference (SPECT, P = 0.17; PET, P = 0.61). Substantial agreement (weighted κ = 0.659) was found between 99mTc-TRODAT-1 and 18F-FDOPA for the detection of presynaptic dopaminergic dysfunction. Specific uptake ratio of striatum correlation between SPECT and PET was statistically significant (r = 0.67; P0.01). A negative but nonsignificant correlation was found between the SURs and HY staging/MDS-UPDRS.Both 99mTc-TRODAT-1 SPECT/CT and 18F-FDOPA PET/CT showed substantial agreement and proved to be potential imaging biomarker for the detection of dopaminergic dysfunction, thus assisting in differentiating early PD/PD and PPS from ET cases.

Tropane alkaloids (TAs) are secondary plant metabolites derived mainly from Solanaceae plant families, with the most virulent invasive species being Datura stramonium. Datura stramonium commonly grows in cereal fields and produce TAs (e.g., hyoscyamine and scopolamine) which may accidentally contaminate cereals (and cereal-based foods) at occasionally high levels. Dietary exposure to TAs can be toxic and depending on the dose ingested can cause outcomes ranging from anticholinergic effects to acute poisoning and death. In 2019, 315 adults became ill and another five adults died in Uganda following consumption of a "Super Cereal" (a fortified blended food) that was later confirmed to be contaminated by TAs-a scenario which provoked this holistic review on TAs in foodstuffs. Thus, this article provides information on the history, development, occurrences, exposures, and human legislative and health benchmarks for TAs. It describes control strategies for reducing TA contamination of agricultural commodities and resultant health implications following consumption of TA contaminated foodstuffs. Adequate application of food safety control measures (including maximum limits) and good practices, from the start of cereal cultivation through to the final stages of manufacturing of food products can aid in the reduction of seeing toxic plants including D. stramonium in cereal fields.

Background Idiopathic normal pressure hydrocephalus can present with parkinsonism. However, abnormalities of the striatal dopamine reuptake transporter are unclear. Objectives To explore presence and features of striatal dopaminergic deficit in subjects with idiopathic normal pressure hydrocephalus as compared to Parkinson's disease (PD) patients and healthy controls. Methods We investigated 50 subjects with idiopathic normal pressure hydrocephalus, 25 with PD, and 40 healthy controls. All participants underwent [123 I]-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane and single-photon emission computed tomography to quantify the striatal dopamine reuptake transporter binding. All subjects with idiopathic normal pressure hydrocephalus underwent a levodopa (l-dopa) challenge test and magnetic resonance imaging to evaluate ventriculomegaly and white matter changes. Gait, cognition, balance, and continence were assessed with the Idiopathic Normal Pressure Hydrocephalus Rating Scale, and parkinsonism with the motor section of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale. All patients completed a 2-year follow-up. Results A total of 62% of patients with idiopathic normal pressure hydrocephalus featured a reduced striatal dopamine reuptake transporter binding, which correlated with the severity of parkinsonism but not with features of ventriculomegaly or white matter changes. Unlike PD, this dopaminergic deficit in idiopathic normal pressure hydrocephalus was more symmetric and prominent in the caudate nucleus. Conclusions Subjects with idiopathic normal pressure hydrocephalus can present a reduction of striatal dopamine reuptake transporter binding, which is consistent with the severity of parkinsonism and qualitatively differs from that found in PD patients. Longitudinal interventional studies are needed to prove a role for striatal dopamine reuptake transporter deficit in the pathophysiology of idiopathic normal pressure hydrocephalus. © 2020 International Parkinson and Movement Disorder Society.

To test the hypothesis that REM sleep behavior disorder (RBD) in early Parkinson's disease (PD) predicts rapid progression of dopaminergic denervation.123I-FP-CIT single photon emission computed tomography (SPECT) scans were performed sequentially at baseline, 1 year, 2 years, and 4 years in 416 de novo patients with PD. RBD screening questionnaire scores5 at baseline placed the participant in the likely-RBD group. Temporal changes in the specific binding ratio (SBR; caudate, putamen. sum of both, striatum) were compared between the likely-RBD and the non-likely-RBD groups for more or less affected striatum with a repeated measure ANOVA.Likely-RBD was reported in 37.7% of the drug-naïve PD patients at baseline. The likely-RBD and non-likely-RBD groups did not have significant differences in the baseline clinical features including gender, age, disease duration, UPDRS motor score, and striatal SBR. Striatal SBR decreased significantly over four years in both groups (P .001). In the analysis of a more affected striatum, striatal SBR decreased significantly faster in the likely-RBD group than in the non-likely-RBD group (P .05 for all), whereas it was not statistically significant for the less affected striatum. The mean striatal SBR value (mean value of both striata), especially the caudate SBR, indicated greater acceleration of denervation in the likely-RBD group than in the non-likely-RBD group over time (P .05).Likely-RBD in PD predicts accelerating dopaminergic denervation, thereby implicating it as a marker for a poor prognosis or distinctive subtype in PD.

Purpose The specific binding ratio (SBR) of 123I-FP-CIT (FP-CIT) in the putamen decreases with age by about 5% per decade and most likely is about 10% higher in females. However, the clinical utility of age and sex correction of the SBR is still a matter of debate. This study tested the impact of age and sex correction on the diagnostic performance of the putamen SBR in three independent patient samples. Methods Research sample: 207 healthy controls (HC) and 438 Parkinson’s disease (PD) patients. Clinical sample A: 183 patients with neurodegenerative parkinsonian syndrome (PS) and 183 patients with non-neurodegenerative PS from one site. Clinical sample B: 84 patients with neurodegenerative PS and 38 patients with non-neurodegenerative PS from another site. Correction for age and sex of the putamen SBR was based on linear regression in the HC or non-neurodegenerative PS, separately in each sample. The area under the ROC curve (AUC) was used as performance measure. Results The putamen SBR was higher in females compared to males (PPMI: 14%, p p p = 0.361). Age-related decline of the putamen SBR ranged between 3.3 and 10.4% (p ≤ 0.019). In subjects ≥ 50 years, age and sex explained p = 0.025) and in clinical sample A (0.9448 versus 0.9519, p = 0.057). There was a small, non-significant AUC increase in clinical sample B (0.9828 versus 0.9743, p = 0.232). Conclusion These findings do not support age and sex correction of the putaminal FP-CIT SBR in the diagnostic workup of parkinsonian syndromes. This most likely is explained by the fact that the proportion of between-subjects variance caused by age and sex is considerably below the symptom threshold of about 50% reduction in neurodegenerative PS.

Species of Hyoscyamus are rich sources of medicinally important tropane alkaloids, which have anticholinergic, antispasmodic and sedative effects and are competitive inhibitors of acetylcholine. The application of nanotechnology and nanomaterials for elicitation is rapidly expanding and recent research indicates that silicon dioxide nanoparticles (SiO2 NPs) can be used as an efficient elicitor to increase the production of hyoscyamine and scopolamine in Hyoscyamus species. Thus, in this work, the effect of SiO2 NPs (0, 25, 50, 100 and 200 mg L−1) with two treatment times (24 and 48 h) on the growth rate, total phenol and flavonoid content (TPC, TFC), antioxidant enzyme activity, tropane alkaloid yield and pmt (putrescine N-methyltransferase) and h6h (hyoscyamine 6 -hydroxylase) gene expression levels in hairy roots of two Hyoscyamus species (H. reticulatus and H. pusillus) was investigated. The highest TPC and TFC accumulation was obtained in H. reticulatus elicited by SiO2 NPs (100 and 200 mg L−1), respectively, at 24 h of treatment. High-performance liquid chromatography (HPLC) revealed the highest amount of hyoscyamine (140.15 μg g−1 FW) and scopolamine (67.71 μg g−1 FW) accumulated in H. reticulatus transformed roots treated with 100 mg L−1 SiO2 NPs at 24 h, with a respective increase of 1212% and 272% compared to non-treated roots. In H. pusillus, the highest hyoscyamine (7.42 μg g−1 FW) and scopolamine (15.56 μg g−1 FW) production (about 82% and 241% higher, respectively, compared to the lowest amounts) was achieved with 25 and 100 mg L−1 SiO2 NPs, respectively, at 48 h of treatment. Semi-quantitative RT-PCR analysis determined the highest expression level of pmt and h6h genes in H. reticulatus transformed roots supplemented with 100 mg L−1 SiO2 NPs.

The specific binding ratio (SBR) is an objective indicator of N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-[123I] iodophenyl) nortropane ([123I]FP-CIT) single-photon emission computed tomography (SPECT) that could be used for the diagnosis of Parkinson’s disease and Lewy body dementia. One of the issues of the SBR analysis is that the setting position of the volume of interest (VOI) may contain cerebral ventricles and cerebral grooves. These areas may become prominent during the brain atrophy analysis; however, this phenomenon has not been evaluated enough. This study thus used Monte Carlo simulations to examine the effect of brain atrophy on the SBR analysis. The brain atrophy model (BAM) used to simulate the three stages of brain atrophy was made using a morphological operation. Brain atrophy levels were defined in the descending order from 1 to 3, with Level 3 indicating to the most severe damage. Projection data were created based on BAM, and the SPECT reconstruction was performed. The ratio of the striatal to background region accumulation was set to a rate of 8:1, 6:1, and 4:1. The striatal and the reference VOI mean value were decreased as brain atrophy progressed. Additionally, the Bolt’s analysis methods revealed that the reference VOI value was more affected by brain atrophy than the striatal VOI value. Finally, the calculated SBR value was overestimated as brain atrophy progressed, and a similar trend was observed when the ratios of the striatal to background region accumulation were changed. This study thus suggests that the SBR can be overestimated in cases of advanced brain atrophy.

Background and Purpose Susceptibility-weighted imaging (SWI) of nigrosome-1 is an emerging and clinically applicable imaging marker for parkinsonism, which can be derived from routinely performed brain MRI. The purpose of the study was to assess whether SWI can be used as a triage tool for more efficient selection of subsequent Dopamine Transporter Scan (DaTSCAN) single-photon emission computed tomography (SPECT). Methods We examined 72 consecutive patients with suspected parkinsonism with both DaTSCAN SPECT and SWI (48 in Philips Ingenia, 24 in GE Signa). Additionally, we examined 24 healthy controls with SWI (14 in Philips Ingenia, 10 in GE Signa). Diagnostic performance of SWI and DaTSCAN SPECT was assessed on the basis of clinical diagnosis, in terms of sensitivity, specificity, and diagnostic accuracy. Results A total of 54 parkinsonism patients (69 years +/- 9, 32 men), 18 nonparkinsonism patients (69.4 years +/- 9, 10 men), and 24 healthy controls (62 years +/- 8, 10 men) were recruited. SWI had a specificity of 92% and a sensitivity of 74%, whereas DaTSCAN SPECT had 83% and 94%, respectively. By preselecting patients with abnormal or inconclusive SWI, the diagnostic performance of DaTSCAN SPECT improved (specificity 100%, sensitivity 95%). Scans from Philips were associated with significantly lower image quality compared to GE (p < .001). The experienced rater outperformed the less experienced one in diagnostic accuracy (82% vs. 68%). Conclusions SWI can be used as triage tool because normal SWI can in most cases rule out parkinsonism. However, the performance of SWI depends on acquisition parameters and raters experience. Funding Agencies|ALF-grants from Region Ostergotland; local LIONS research fund

Background Idiopathic Parkinson's disease (PD) is characterized by clinical motor symptoms including hypokinesia, rigidity and tremor. In addition to the movement disorder, cognitive deficits are commonly described. In the present study, we applied FP-CIT SPECT to investigate the impact of nigrostriatal dopaminergic degeneration on cognitive function in PD patients. Methods Fifty-four PD patients underwent [123I]FP-CIT SPECT and CERAD (Consortium to Establish a Registry for Alzheimer's Disease) testing. FP-CIT SPECT visualized the density of presynaptic dopamine transporters in both striata, each subdivided into a limbic, executive and sensorimotor subregion according to the atlas of Tziortzi et al (Cereb Cortex 24, 2014, 1165). CERAD testing quantified cognitive function. Results In the CERAD testing, PD patients exhibited deficits in the domains of semantic memory, attention, visuospatial function, non-verbal memory and executive function. After correction for multiple testing, the performance of the subtests Figure Recall and Trail-Making Test A correlated significantly with FP-CIT uptake into the ipsilateral executive subregion. The performance of the subtest Figure Saving correlated significantly with FP-CIT uptake into the contralateral executive subregion. Conclusions The significant correlation between cognitive function and density of nigrostriatal dopamine transporters, as assessed by FP-CIT SPECT, indicate that striatal dopaminergic pathways-primarily the executive striatal subregion-are relevant to cognitive processing in PD.

OBJECTIVE 18 F-FP-CIT and 123 I-FP-CIT are widely used radiotracers in molecular imaging for Parkinson's disease (PD) diagnosis. Compared with 123 I-FP-CIT, 18 F-FP-CIT has superior tracer kinetics. We aimed to conduct a meta-analysis to assess the efficacy of using 18 F-FP-CIT positron emission tomography (PET) and 123 I-FP-CIT single-photon emission computed tomography (SPECT) of dopamine transporters in patients with PD in order to provide evidence for clinical decision-making. METHODS We searched the PubMed, Embase, Wanfang Data, and China National Knowledge Infrastructure databases to identify the relevant studies from the time of inception of the databases to 30 April 2020. We identified six PET studies, including 779 patients with PD and 124 healthy controls, which met the inclusion criteria. Twenty-seven SPECT studies with 1244 PD patients and 859 controls were also included in this meta-analysis. RESULTS Overall effect-size analysis indicated that patients with PD showed significantly reduced 18 F-FP-CIT uptake in three brain regions [caudate nucleus: standardized mean difference (SMD) = -1.71, Z = -3.31, P = 0.0009; anterior putamen: SMD = -3.71, Z = -6.26, P

Parkinsonism has heterogeneous nature, showing distinctive patterns of disease progression and prognosis. We aimed to find clusters of parkinsonism based on 18F‐fluoropropyl‐carbomethoxyiodophenylnortropane (FP‐CIT) PET as a data‐driven approach to evaluate heterogenous dopaminergic neurodegeneration patterns. Two different cohorts of patients who received FP‐CIT PET were collected. A labeled cohort (n = 94) included patients with parkinsonism who underwent a clinical follow‐up of at least 3 years (mean 59.0 ± 14.6 months). An unlabeled cohort (n = 813) included all FP‐CIT PET data of a single‐center. All PET data were clustered by a dimension reduction method followed by hierarchical clustering. Four distinct clusters were defined according to the imaging patterns. When the diagnosis of the labeled cohort of 94 patients was compared with the corresponding cluster, parkinsonism patients were mostly included in two clusters, cluster “0” and “2.” Specifically, patients with progressive supranuclear palsy were significantly more included in cluster 0. The two distinct clusters showed significantly different clinical features. Furthermore, even in PD patients, two clusters showed a trend of different clinical features. We found distinctive clusters of parkinsonism based on FP‐CIT PET‐derived heterogeneous neurodegeneration patterns, which were associated with different clinical features. Our results support a biological underpinning for the heterogeneity of neurodegeneration in parkinsonism.

OBJECTIVE: To describe (123)I-FP-CIT (DAT scan) SPECT findings in progressive apraxia of speech (PAOS) patients and to compare those findings to progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). BACKGROUND: PAOS is a neurodegenerative syndrome in which patients present with apraxia of speech, a motor speech disorder affecting programming and planning of speech. Patients with PAOS predictably develop Parkinsonism. DAT scan is a neuroimaging tool that assesses the integrity of presynaptic dopamine transporters in basal ganglia and is usually abnormal in PSP and CBS. METHODS: As a part of an NIH-funded grant, we performed a DAT scan on 17 PAOS patients early in the disease course. DaTQUANT software was used to quantify uptake in left and right caudate and anterior/posterior putamen, with striatum to background ratios (SBRs). The PAOS cohort was compared to 15 PSP and 8 CBS patients. RESULTS: Five PAOS patients (29%) showed abnormalities in at least one striatal region on DAT scan. When the five PAOS patients with abnormal DAT was compared to the PSP and CBS patients, the only difference observed was lower uptake in the posterior putamen in PSP (p=0.03). There were no differences is putamen/caudate ratio or in symmetry of uptake, across all groups. There was also no difference in MDS-UPDRS-III scores between PAOS patients with and without abnormal DAT scans (p=0.56). CONCLUSIONS: Abnormal DAT scan is observed early in the disease course in approximately 30% of PAOS patients, with striatal abnormalities similar to those in PSP and CBS.

The study compared effectiveness of intranasal administration of glypin (human recombinant modified glucagon-like peptide-1) and reference drug Victoza in BALB/c mice. The minimum effective dose of intranasal glypin was 0.5 mg/kg, and a 2-fold elevation of this dose increased the parameters of glypin activity up to the maximal levels. During the first 2 h after intranasal administration, the effectiveness of glypin greatly surpassed that of Victoza. Duration of action and the time course of antihyperglycemic activity of intranasal glypin (1 mg/kg) matched to the best parameters attained during its subcutaneous application. A high effectiveness of intranasal glypin opens the vistas to its further examination and employment.

Background Neuropathological data and nuclear medicine imaging show extensive serotonergic impairment in Parkinson’s disease (PD). We undertook a case-controlled analysis of 123I-FP-CIT SPECT images to measure extrastriatal serotonergic transporters (SERT) in PD using the Parkinson’s Progression Markers Initiative (PPMI) cohort. Methods We included all PD (n = 154) and Control subjects (n = 62) with available 123I-FP-CIT SPECT imaging and high-resolution T1-weighted MRI for coregistration (PD: mean age 61.6 years, 62% male, disease duration 26 months, MDS-UPDRS III score 22). 123I-FP-CIT SPECT images were processed with PETPVE12 using an exploratory voxel-wise analysis including partial-volume effect correction. Linear regressions were performed in the PD group to assess correlations between region of interest 123I-FP-CIT uptake and clinical motor and non-motor impairment. Results Compared to Controls, PD exhibited an uptake reduction in bilateral caudate nucleus, putamen, insula, amygdala and right pallidum (family-wise error (FWE)-corrected p p = 0.022), we found a trend association between higher geriatric depression scale and lower pallidum uptake (p = 0.09). Higher SCOPA-AUT gastrointestinal subscore was associated with lower uptake in mean putamen and caudate nucleus (p = 0.01 to 0.03), whereas urological subscore was inversely correlated with mean caudate nucleus, putamen, and pallidum uptake (p = 0.002 to 0.03). REM sleep behaviour disorder screening questionnaire was associated with lower 123I-FP-CIT binding in caudate nucleus, putamen and pallidum (all p p > 0.45) or excessive daytime sleepiness (all p > 0.29). Conclusions In addition to the well-established striatal deficit, this study provides evidence of a major extrastriatal 123I-FP-CIT impairment, and therefore of an altered serotonergic transmission in early PD.

Datura stramonium, Atropa belladonna, Hyoscyamus niger, and Scopolia carniolica are all temperate plants from the family Solanaceae, which as a result of their anticholinergic tropane alkaloids, hyoscyamine/atropine and scopolamine, have caused many cases of poisoning around the world. Despite the danger these nightshade plants represent, the literature often presents incomplete cases lacking in details and filled with ambiguity, and reviews on the topic tend to be limited in scope. Many also point to a gap in knowledge of these plants among physicians. To address this, the following review focuses on intoxications involving these plants as reported in the literature between 1966 and 2018, with brief mention to pertinent related plants to contextualise and provide a fuller picture of the situation surrounding the presently discussed temperate plants. Analysis of the literature displays that D. stramonium is largely associated with drug use among teens while A. belladonna is primarily ingested as a result of the berries being mistaken for edible fruits. H. niger was found to be largely ingested when mistaken for other plants, and S. carniolica was the cause of incredibly few intoxications.

Konstantinos Kostikas,1 Theodoros I Vassilakopoulos,2,3 Nikos Tzanakis,4 Athanasios K Konstantinidis,1 Epameinondas N Kosmas,5 Spyros Papiris,6 Paschalis Steiropoulos,7 Effrosyni D Manali,6 Stylianos A Michaelides8,†, Grigorios Daskos9 1Respiratory Medicine Department, University Hospital of Ioannina, Ioannina, Greece; 2Pulmonary and Critical Care Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 3Third Department of Critical Care Medicine, Evgenideio Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 4Department of Respiratory Medicine, University Hospital of Heraklion, Medical School, University of Crete, Crete, Greece; 5Department of Pulmonary Medicine, Metropolitan Hospital, Athens, Greece; 6Second Pulmonary Medicine Department, General University Hospital “Attikon”, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 7Pulmonology Clinic Medical School, Democritus University of Thrace/University General Hospital, Alexandroupolis, Greece; 8Department of Occupational Lung Disease and Tuberculosis, “Sismanogleio-Amalia Fleming” General Hospital, Athens, Greece; 9MENARINI HELLAS, Athens, Greece†Stylianos A Michaelides passed away on September 14, 2019Correspondence: Konstantinos KostikasRespiratory Medicine Department, University of Ioannina School of Medicine, Leoforos Stavrou Niarchou, Ioannina 45500, GreeceTel +30-2651007536Email ktkostikas@gmail.comPurpose: This multicenter, prospective, observational study aimed to supplement real-world evidence on the effects of aclidinium bromide on the quality of life (QoL), symptoms, and activity impairment of patients with COPD.Patients and Methods: Eligible patients were ≥ 40 years of age, newly initiated on aclidinium bromide as monotherapy or add-on therapy according to the product’s approved label. Patient-reported COPD assessment test (CAT), the severity of symptoms and their impact on daily activities, and the features of the Genuair® inhaler device were assessed at enrollment and at 12 weeks post-treatment onset.Results: Between 13 March 2015 and 29 January 2016, 285 eligible consenting patients (76.3% males; median age: 69.0 years; 26.0% newlydiagnosed with COPD) were enrolled by 15 hospital-based respiratory medicine specialists in Greece. Aclidinium bromide was initiated as add-on therapy to other inhaled maintenance medications in 73.1% of evaluable patients. The median (interquartile range [IQR]) baseline CAT score decreased from 14.0 (9.0– 20.0) to 10.0 (6.0– 15.0) points (p< 0.001) after 12 weeks of treatment, with 76.5% of the patients achieving a ≥ 2-point decrease. The severity of night-time and early-morning symptoms, assessed using a 5-point Likert-type scale, decreased from a median (IQR) of 1.0 (0.0– 2.0) to 0.0 (0.0– 1.0), and from 2.0 (1.0– 2.0) to 1.0 (1.0– 2.0), respectively (p< 0.001 for both). In patients with paired data, the prevalence of at least moderate night-time symptoms, early-morning symptoms, and daily activity impairment decreased from 28.2% to 19.1%, from 63.6% to 34.2%, and from 59.5% to 38.7%, respectively (p< 0.001 for all). Inhaler device features were assessed as “very good”/“good” by more than 90% of the patients. The adverse drug reaction rate was 1.4%.Conclusion: The study provides real-world evidence on the beneficial effects of aclidinium bromide on the patients’ QoL, symptom severity, and daily activity impairment, which are complemented by a favorable safety profile and high patient satisfaction with the inhaler device.Keywords: aclidinium, chronic obstructive pulmonary disease, COPD assessment test, daily activities, quality of life, symptoms

INTRODUCTION Symptom laterality is one of the main characteristics of Parkinson disease (PD) and reported to be associated with motor and nonmotor symptom severity and prognosis. This study aimed to evaluate the changes of laterality after deep brain stimulation (DBS) and the association between dopamine transporter SPECT using I FP-CIT (DAT SPECT) and symptom laterality in PD before and after DBS. METHODS Nineteen patients with PD who received bilateral subthalamic nucleus DBS were enrolled. The clinical scores including Unified Parkinson Disease Rating Scale (UPDRS) and Hoehn and Yahr were evaluated at baseline, 6 months, and 1 year after DBS. Also, the patients underwent DAT SPECT before and 6 months and 1 year after DBS. Symptom and DAT laterality indices were determined based on the UPDRS part 3 and DAT SPECT, respectively. The association between DAT and symptom laterality was assessed at baseline and 6 months and 1 year after DBS. RESULTS At baseline, 11, 6, and 2 among 19 patients had left-side-dominant, right-side-dominant, and symmetric motor symptom, respectively. Among 19 patients, there were 10 patients who showed changed symptom laterality within 1 year after DBS. The agreement between symptom laterality and DAT laterality was good to excellent at baseline and 6 months and 1 year after DBS (weighted κ = 0.742, 0.736, and 0.813). Furthermore, symptom and DAT laterality indices showed significant correlation at baseline (r = 0.542, P = 0.02), 6 months (r = 0.579, P = 0.01), and 1 year after DBS (r = 0.689, P = 0.02). Symptom laterality could be determined by DAT laterality index with areas under curve of 0.833 (P = 0.045), 0.982 (P < 0.001), and 1.000 (P < 0.001) at baseline and 6 and 12 months after DBS, respectively. CONCLUSIONS The symptom laterality could be altered after DBS and was well correlated with laterality evaluated by DAT SPECT. An objective evaluation of laterality using DAT SPECT would be helpful for the management of patients with PD especially for adjusting the DBS programming for fine balancing of the asymmetric symptom after DBS. The large-scale study is warranted for validation of this result.

Neuroinflammation in Parkinson’s disease (PD) is known to play a pivotal role in progression to neuronal degeneration. It has been reported that colony-stimulation factor 1 receptor (CSF-1R) inhibition can effectively deplete microglia. However, its therapeutic efficacy in PD is unclear still now. To elucidate this issue, we examined the contribution of microglial depletion to PD by behavioral testing, positron emission tomography (PET) imaging, and immunoassays in sham, PD, and microglial depletion PD model (PLX3397 was administered to PD groups, with n = 6 in each group). The microglial depletion in PD model showed improved sensory motor function and depressive-like behavior. NeuroPET revealed that PLX3397 treatment resulted in partial recovery of striatal neuro-inflammatory functions (binding values of [18F]DPA-174 for PD, 1.47 ± 0.12, p 0.05). Western blotting for microglia showed similar changes. Microglial depletion has inflammation-related therapeutic effects, which have beneficial effects on motor and nonmotor symptoms of PD.

PURPOSE The present study investigated possible associations between cortical dysfunction/degeneration as measured by F-FDG PET and nigrostriatal degeneration according to the specific I-FP-CIT binding ratio (SBR) in striatal subregions defined by striato-cortical anatomical connectivity in Parkinson disease (PD) patients. MATERIALS AND METHODS The study included 41 patients (61.4 ± 12.8 years) with PD-typical reduction of striatal FP-CIT SBR and no sign of atypical parkinsonian syndrome on FDG PET. FP-CIT SBR was determined separately in the cognitive (composite of executive and limbic) and sensorimotor part of the striatum according to the Oxford-GSK-Imanova Striatal Connectivity Atlas. Scaled FDG uptake was tested voxelwise for correlation with FP-CIT SBR (familywise error corrected P < 0.05). RESULTS A large cluster (17.6 mL) of significant correlation of scaled FDG uptake with FP-CIT SBR in the cognitive part of the striatum, corrected for SBR in the sensorimotor part, was detected in the bilateral medial frontal cortex and the anterior cingulate cortex (partial correlation coefficient R = 0.767); small clusters were detected in ipsilateral caudate and ipsilateral thalamus. There was a small contralateral occipital cluster (3.0 mL) of significant correlation between FDG uptake and sensorimotor SBR corrected for cognitive SBR (R = 0.709). CONCLUSIONS The correlation between nigrostriatal degeneration in the cognitive striatum and reduced cerebral glucose metabolism in the medial parts of the frontal cortex including the anterior cingulate suggests that nigrostriatal degeneration is specifically involved in the pathogenesis of cognitive deficits associated with medial frontal dysfunction such as impaired inhibitory control.

Some medicinal plants of the Solanaceae produce pharmaceutical tropane alkaloids (TAs), such as hyoscyamine and scopolamine. Littorine is a key biosynthetic intermediate in the hyoscyamine and scopolamine biosynthetic pathways. However, the mechanism underlying littorine formation from the precursors phenyllactate and tropine is not completely understood. Here, we report the elucidation of littorine biosynthesis through a functional genomics approach and functional identification of two novel biosynthesis genes that encode phenyllactate UDP-glycosyltransferase (UGT1) and littorine synthase (LS). UGT1 and LS are highly and specifically expressed in Atropa belladonna secondary roots. Suppression of either UGT1 or LS disrupted the biosynthesis of littorine and its TA derivatives (hyoscyamine and scopolamine). Purified His-tagged UGT1 catalysed phenyllactate glycosylation to form phenyllactylglucose. UGT1 and LS co-expression in tobacco leaves led to littorine synthesis if tropine and phenyllactate were added. This identification of UGT1 and LS provides the missing link in littorine biosynthesis. The results pave the way for producing hyoscyamine and scopolamine for medical use by metabolic engineering or synthetic biology.

Glabellar tap or reflex (GR) is an old bedside clinical test used in the diagnostics of Parkinson’s disease (PD), but its diagnostic value is unclear. This study examines the diagnostic validity and reliability of GR in PD in relation to brain dopaminergic activity. GR was performed on 161 patients with PD, 47 patients with essential tremor (ET) and 40 healthy controls immediately prior to dopamine transporter (DAT) [123I]FP-CIT SPECT scanning. The binding ratios were investigated with consideration of the GR result (normal/abnormal). In addition, the consistency of the GR was investigated with 89 patients after a mean follow-up of 2.2 years. PD and ET patients had higher GR scores than healthy controls (p p = 0.09). There were no differences in the ratio of abnormal to normal GRs between the PD and ET groups (73% vs. 64% abnormal, respectively, p = 0.13) or in DAT binding between PD patients with abnormal and normal GRs (p > 0.36). Over follow-up, the GR changed from abnormal to normal in 20% of PD patients despite the presence of clinically typical disease. The sensitivity and specificity of GR for differentiating PD from ET were 78.3% and 36.2%, respectively. Although GR has been used by clinicians in the diagnostics of PD, it does not separate PD from ET. It also shows considerable inconsistency over time, and abnormal GR has no relationship with dopamine loss. Its usefulness should be tested for other clinical diagnostic purposes.

This study used explainable artificial intelligence for data-driven identification of extrastriatal brain regions that can contribute to the interpretation of dopamine transporter SPECT with 123I-FP-CIT in parkinsonian syndromes. A total of 1306 123I-FP-CIT-SPECT were included retrospectively. Binary classification as ‘reduced’ or ‘normal’ striatal 123I-FP-CIT uptake by an experienced reader served as standard-of-truth. A custom-made 3-dimensional convolutional neural network (CNN) was trained for classification of the SPECT images with 1006 randomly selected images in three different settings: “full image”, “striatum only” (3-dimensional region covering the striata cropped from the full image), “without striatum” (full image with striatal region removed). The remaining 300 SPECT images were used to test the CNN classification performance. Layer-wise relevance propagation (LRP) was used for voxelwise quantification of the relevance for the CNN-based classification in this test set. Overall accuracy of CNN-based classification was 97.0%, 95.7%, and 69.3% in the “full image”, “striatum only”, and “without striatum” setting. Prominent contributions in the LRP-based relevance maps beyond the striatal signal were detected in insula, amygdala, ventromedial prefrontal cortex, thalamus, anterior temporal cortex, superior frontal lobe, and pons, suggesting that 123I-FP-CIT uptake in these brain regions provides clinically useful information for the differentiation of neurodegenerative and non-neurodegenerative parkinsonian syndromes.

The presynaptic dopamine transporter (DAT) modulates the uptake of dopamine by regulating its concentration in the central nervous system. We aimed to evaluate the DAT binding potential (DAT-BP) in a sample of healthy Brazilians through technetium-99 metastable TRODAT-1 single-photon emission computed tomography imaging. We selected 126 healthy individuals comprising 72 men and 54 women, aged 18 to 80 years. We conducted semi-quantitative evaluation in transaxial slices, following which we identified the regions of interest in the striatal region using the occipital lobe as a region of non-specific DAT-BP. We found a decrease in DAT-BP in healthy individuals aged over 30 years, culminating in a 42% mean reduction after 80 years. There was no difference in the decrease by age group between the right (linear regression test [R2] linear = 0.466) and left striatum (R2 linear = 0.510). Women presented a higher DAT-BP than men (women: R2 linear = 0.431; men: R2 linear = 0.457); nonetheless, their decrease by age group was equal to that in men. Our study sheds light on important DAT-BP findings in healthy Brazilian subjects. Our results will facilitate understanding of brain illnesses that involve the dopamine system, such as neuropsychiatric disorders.

Background Beta-blocker therapies for cardiovascular comorbidities are often withheld in patients with chronic obstructive pulmonary disease (COPD) due to potential adverse effects on airway obstruction. We carried out a post hoc analysis to determine the efficacy and safety of aclidinium in patients with moderate-to-very severe COPD and increased cardiovascular risk receiving beta-blockers at baseline versus non-users. Methods ASCENT-COPD was a Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study. Patients were randomized 1:1 to aclidinium or placebo twice-daily for up to 3 years. Outcomes included risk of (time to first) major adverse cardiovascular events (MACE), all-cause mortality, and lung function over 3 years, and exacerbations over 1 year. Results Of 3589 patients, 1269 (35.4%) used beta-blockers and 2320 (64.6%) were non-users at baseline. Aclidinium did not statistically increase the risk of MACE (beta-blocker user: hazard ratio 1.01 [95% CI 0.62–1.64]; non-user: 0.80 [0.51–1.24]; interaction P = 0.48) or all-cause mortality (beta-blocker user: 1.13 [0.78–1.64]; non-user: 0.89 [0.62–1.26]; interaction P = 0.35), in patients using beta-blockers. Aclidinium reduced annualized rate of moderate-to-severe COPD exacerbation (beta-blocker user: rate ratio 0.75 [95% CI 0.60–0.94, P = 0.013]; non-user: 0.79 [0.67–0.93, P = 0.005]), delayed time to first exacerbation, and improved lung function versus placebo. There was greater trough FEV1 benefit in beta-blocker users versus non-users (least squares mean difference at 52 weeks: 111 mL [95% CI 74 mL–147 mL] versus 69 mL [42 mL–97 mL]; interaction P = 0.041). Conclusions This post hoc analysis supports long-acting anti-muscarinic use with concomitant beta-blockers in patients with moderate-to-very severe COPD and cardiovascular comorbidity. Trial registration: ClinicalTrials.gov, NCT01966107, Registered 16 October 2013, https://clinicaltrials.gov/ct2/show/NCT01966107.

Microbial biosynthesis of plant natural products (PNPs) can facilitate access to valuable medicinal compounds and derivatives. Such efforts are challenged by metabolite transport limitations, which arise when complex plant pathways distributed across organelles and tissues are reconstructed in unicellular hosts without concomitant transport machinery. We recently reported an engineered yeast platform for production of the tropane alkaloid (TA) drugs hyoscyamine and scopolamine, in which product accumulation is limited by vacuolar transport. Here, we demonstrate that alleviation of transport limitations at multiple steps in an engineered pathway enables increased production of TAs and screening of useful derivatives. We first show that supervised classifier models trained on a tissue-delineated transcriptome from the TA-producing plant Atropa belladonna can predict TA transporters with greater efficacy than conventional regression- and clustering-based approaches. We demonstrate that two of the identified transporters, AbPUP1 and AbLP1, increase TA production in engineered yeast by facilitating vacuolar export and cellular reuptake of littorine and hyoscyamine. We incorporate four different plant transporters, cofactor regeneration mechanisms, and optimized growth conditions into our yeast platform to achieve improvements in de novo hyoscyamine and scopolamine production of over 100-fold (480 μg/L) and 7-fold (172 μg/L). Finally, we leverage computational tools for biosynthetic pathway prediction to produce two different classes of TA derivatives, nortropane alkaloids and tropane N-oxides, from simple precursors. Our work highlights the importance of cellular transport optimization in recapitulating complex PNP biosyntheses in microbial hosts and illustrates the utility of computational methods for gene discovery and expansion of heterologous biosynthetic diversity.

Introduction: Aclidinium/formoterol is a long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) dual bronchodilator used as a maintenance treatment for patients with chronic obs...

We report the accumulation of 99mTc-TRODAT-1 in the region of subacute cerebral ischemic infarction in an 81-year-old woman with Parkinson disease. The dopamine transporter SPECT imaging was performed on the 15th day after the onset of acute cerebral ischemic clinical symptoms. Overexpression of dopamine transporters after infarction in subacute phase may explain the accumulation.

Introduction Long-acting muscarinic antagonists (LAMAs), long-acting β2-agonists (LABAs), inhaled corticosteroids (ICS), and their combinations, are recommended for the treatment of chronic obstructive pulmonary disease (COPD). This study aimed to determine whether the safety and efficacy of aclidinium bromide differs by baseline maintenance LABA and ICS therapies. Methods ASCENT-COPD was a phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study of patients with moderate-to-very severe COPD and increased cardiovascular risk. Patients were randomized 1:1 to receive aclidinium 400 μg or placebo twice daily, via a multidose dry-powder inhaler for up to 3 years. Outcomes included time to first major adverse cardiovascular events (MACE), all-cause mortality, change from baseline in trough forced expiratory volume in 1 s (FEV1), and COPD assessment test (CAT) total score over 3 years, and annual moderate-to-severe COPD exacerbation rate in patients receiving aclidinium or placebo with maintenance LABA monotherapy, ICS monotherapy, LABA + ICS (fixed/free), or no maintenance therapy (neither LABA nor ICS) at baseline. Results A total of 3589 patients were included (LABA, n = 227; ICS, n = 290; LABA + ICS, n = 2058; no maintenance, n = 1130). Aclidinium did not increase the risk of MACE or all-cause mortality versus placebo, regardless of baseline maintenance treatment. Reductions in moderate-to-severe exacerbation rates were observed with aclidinium versus placebo in all subgroups [LABA 43% (P = 0.046); ICS 25% (P = 0.202); LABA + ICS 22% (P = 0.003); no maintenance 18% (P = 0.130)]. Aclidinium improved morning trough FEV1 irrespective of baseline therapy and CAT total scores, except for LABA and ICS subgroups, versus placebo at several time points. Conclusion In patients with moderate-to-severe COPD and CV risk factors, the addition of aclidinium to maintenance therapy with LABA or LABA + ICS provided further benefit. Trial Registration ClinicalTrials.gov identifier NCT01966107. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01878-5.

Corticobasal syndrome (CBS) is characterized by a slow progressive cognitive decline, apraxia, myoclonus, dystonia, and parkinsonism. We experienced a rapidly progressing CBS patient (onset to bed-ridden within 2 years) presenting only with resting tremor but showing complete unilateral loss of dopamine transporter binding. This case exhibited distinct FDG PET findings involving the unilateral severe anterior frontal cortex, caudate nucleus, and contralateral cerebellum, which is different from classical CBS. However, to date, no detailed serial functional imaging study has been performed in rapidly progressing CBS, so these FDG PET and CIT PET findings may help clinicians to recognize this fulminant type of corticobasal degeneration.

We aimed to evaluate the white matter hyperintensity (WMH) effect on dopamine transporter availability (DAT) of striatum. A total of 48 patients who showed visually normal F-18 FP-CIT uptake were included in this study. Each FP-CIT image were pre-processed using SPM12. Co-registration and spatial normalization of FP-CIT image conducted using T1-weighted magnetic resonance imaging (MRI). And then smoothing of normalized FP-CIT image was performed. Intensity normalization was performed using cerebellum as a reference region. With pre-defined volume of interest template, the specific binding ratio (SBR) of both side of caudate nucleus and putamen was calculated. Fluid attenuated inversion recovery MRI scans were used to evaluate WMH number and volume. SBRs of left and right caudate nucleus were correlated with age (r = − 0.615; p

Water bloom-forming cyanobacteria have a severe impact on freshwater quality. Although some cyanobacterial toxins such as microcystins have been studied extensively, other toxins like anatoxin-a (ATX) and their structural analogs - as well as cyanobacterial taxa producing these toxins remain to be explored in detail. The present study investigated levels of ATX, CYN and their homologs along with the occurrence of anaC and cyrJ genes in water blooms in 16 sites in the Czech Republic that were pre-selected concerning the presence of potential toxin producers. Besides, we also studied toxins and genes in a series of strains available in our laboratories. ATX and its congener HATX were detected in 5 natural biomass samples from the Czech Republic (maximum concentration 2.8 micrograms per gram d.w.). Interestingly, the anaC gene coding for ATX production was not detected in any of these toxin-positive biomass samples. The concentrations of ATX congeners in cyanobacterial laboratory strains were about 10-times higher than those of the original ATX, which calls for further research addressing levels and hazards of ATX analogs. Regarding the CYN and 7-deoxyCYN (other CYN congeners were not analyzed in this study) - these toxins were identified in a single small pond in the Czech Republic at concentrations 4.3 and 2.7 micrograms per gram of biomass d.w., respectively (corresponded to dissolved concentrations higher than 1 microgram per liter). The CYN-positive sample was dominated by CYN-producing taxa Raphidiopsis (basionym Cylindrospermopsis) and Cuspidothrix. We also confirmed the presence of a specific cyrJ gene in this natural bloom sample. To our knowledge, this is the first study pointing to Raphidiopsis (Cylindrospermopsis) and Cuspidothrix as producers of CYN in Europe. This observation calls for further research because of their increasing occurrence in (Central) Europe along with the global change. The present study demonstrates the importance of using combined (taxonomical, analytical, and molecular) approaches in the assessment of hazardous cyanobacteria and their toxins in freshwaters.

An 85-year-old woman visited our hospital with repetitive diarrhea, nausea, and anorexia, as well as aggressive behavior. The neurologist decided to perform dopamine transporter imaging (F-FP-CIT PET/CT) for accurate diagnosis, taking into account the potential adverse effects of L-dopa that the patient had been taking for a long time. The uptake of dopamine transporter in the bilateral basal ganglia was well preserved, but reduced uptake in the left parotid gland was incidentally detected. A subsequent salivary scan showed reduced uptake in the left parotid gland with the same pattern as that on F-FP-CIT PET/CT.

PURPOSE OF THE REPORT Oxidative stress is a leading factor in the pathogenesis of idiopathic Parkinson disease (IPD). Two intrinsic antioxidative molecules, bilirubin and uric acid, are known to protect dopaminergic neurons from oxidative stress in IPD. The objective of this study was to determine the relationship between basal serum levels of 2 molecules and dopaminergic deficit assessed by dopamine transporter imaging with F-fluorinated-N-3-fluoropropyl-2-β-carboxymethoxy-3-β-(4-iodophenyl)nortropane ([F]FP-CIT) PET/CT in patients with early-stage drug-naive IPD. METHODS Cases of IPD patients who possess the levels of uric acid and bilirubin within a month from [F]FP-CIT PET/CT from January 2011 to December 2016 were retrospectively reviewed. As a control, the same criteria applied to patients with essential tremor (ET). PET images were analyzed using volume-of-interest templates for 12 striatal subregions and 1 occipital area, and the specific-to-nonspecific binding ratio (SNBR) was calculated. RESULTS One hundred five patients with drug-naive, early-stage IPD and 62 patients with ET were finally included. Levels of bilirubin were significantly higher in the IPD group than in controls (P = 0.026), and bilirubin level was the factor showing the most correlations with SNBR in IPD (P < 0.001), whereas uric acid showed no such difference or relationship. Furthermore, levels of bilirubin showed a positive correlation with SNBR in more affected posterior putamen in the IPD group (Pearson correlation coefficient, ρ = 0.456; P < 0.001), but a negative one in the ET group (ρ = -0.440, P < 0.001). CONCLUSIONS Bilirubin, not uric acid, was the most significant antioxidant marker for dopaminergic deficit in early-stage drug-naive IPD assessed by [F]FP-CIT PET/CT.

The skeleton of tropane alkaloids is derived from ornithine-derived N-methylpyrrolinium and two malonyl-CoA units. The enzymatic mechanism that connects N-methylpyrrolinium and malonyl-CoA units remains unknown. Here, we report the characterization of three pyrrolidine ketide synthases (PYKS), AaPYKS, DsPYKS, and AbPYKS, from three different hyoscyamine- and scopolamine-producing plants. By examining the crystal structure and biochemical activity of AaPYKS, we show that the reaction mechanism involves PYKS-mediated malonyl-CoA condensation to generate a 3-oxo-glutaric acid intermediate that can undergo non-enzymatic Mannich-like condensation with N-methylpyrrolinium to yield the racemic 4-(1-methyl-2-pyrrolidinyl)-3-oxobutanoic acid. This study therefore provides a long sought-after biosynthetic mechanism to explain condensation between N-methylpyrrolinium and acetate units and, more importantly, identifies an unusual plant type III polyketide synthase that can only catalyze one round of malonyl-CoA condensation., Tropane alkaloids are medicinally significant plant metabolites generated by an unusual condensation of ornithine-derived and malonyl-CoA precursors. Here, Huang et al. show that pyrrolidine ketide synthase catalyzes a single round of condensation, which is followed by a non-enzymatic Mannich-like condensation.

We investigated the effects of maturation on dopamine transporter (DAT) availability in the rat via longitudinal monitoring with positron emission tomography (PET). Eight 5-week-old male Sprague-Dawley rats (113-186 g) were used. Four In CPu, SBRs at 5 weeks (3.25 ± 0.66) were lower than those at 10 weeks (4.59 ± 0.78, p = 0.1151) and at 15 weeks (5.56 ± 0.92, p = 0.0182). In NAc, SBRs at 5 weeks (1.41 ± 0.47) were lower than those at 10 weeks (2.03 ± 0.36, p = 0.1960) and at 15 weeks (2.43 ± 0.50, p = 0.0427). SBRs in CPu and NAc significantly increased with maturation until 15 weeks. However, differences in SBR between 15 and 20 weeks were not significant. Striatal DAT availability increases until 15 weeks postnatally, then remains stable, reflecting maturation of the dopaminergic system in rats. Wir untersuchten die Auswirkungen der Reifung auf die Verfügbarkeit von Dopamintransportern (DAT) in der Ratte durch longitudinale Beobachtung mit Positronen-Emissions-Tomografie (PET). Es wurden acht 5 Wochen alte männliche Sprague-Dawley-Ratten (113–186 g) verwendet. Vier 18F-FP-CIT PET-Aufnahmen wurden nach 5, 10, 15 und 20 Wochen durchgeführt. Die PET-Bilder zu Studienbeginn wurden manuell mit dem eingebauten Magnetresonanztomografie-Template fusioniert. Volumes of Interest (VOIs) wurden manuell definiert, indem ein sphärischer Bereich mit der maximalen Zählrate um den Hotspot gelegt wurde. VOIs wurden auf den bilateralen Caudatus und Putamen (CPu), Nucleus accumbens (NAc) und das Kleinhirn gelegt. Die spezifischen Bindungsratios (SBRs) wurden wie folgt berechnet: (mittlere Aufnahme der bilateralen Ziele – mittlere Aufnahme des bilateralen Kleinhirns)/(mittlere Aufnahme des bilateralem Kleinhirn). Im CPu waren die SBRs nach 5 Wochen (3,25 ± 0,66) niedriger als nach 10 Wochen (4,59 ± 0,78, p = 0,1151) und nach 15 Wochen (5,56 ± 0,92, p = 0,0182). Im NAc waren die SBRs nach 5 Wochen (1,41 ± 0,47) niedriger als nach 10 Wochen (2,03 ± 0,36, p = 0,1960) und nach 15 Wochen (2,43 ± 0,50, p = 0,0427). Die SBRs in CPu und NAc nahmen mit der Reifung bis 15 Wochen signifikant zu. Allerdings waren die Unterschiede in der SBR zwischen 15 und 20 Wochen nicht signifikant. Die Verfügbarkeit von striatalen DAT steigt bis 15 Wochen nach der Geburt an und bleibt dann stabil, was die Reifung des dopaminergen Systems bei Ratten widerspiegelt.

ObjectiveTo investigate the effect of polygenic load on the progression of striatal dopaminergic dysfunction in patients with Parkinson disease (PD).MethodsUsing data from 335 patients with PD in the Parkinson's Progression Markers Initiative (PPMI) database, we investigated the longitudinal association of PD-associated polygenic load with changes in striatal dopaminergic activity as measured by 123I-N-3-fluoropropyl-2-β-carboxymethoxy-3β-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT over 4 years. PD-associated polygenic load was estimated by calculating weighted genetic risk scores (GRS) using 1) all available 27 PD-risk single nucleotide polymorphisms (SNPs) in the PPMI database (GRS1) and 2) 23 SNPs with minor allele frequency >0.05 (GRS2).ResultsGRS1 and GRS2 were correlated with younger age at onset in patients with PD (GRS1, Spearman ρ = −0.128, p = 0.019; GRS2, Spearman ρ = −0.109, p = 0.047). Although GRS1 did not show an association with changes in striatal 123I-FP-CIT availability, GRS2 was associated with a slower decline of striatal dopaminergic activity (interactions with disease duration in linear mixed model; caudate nucleus, estimate = 0.399, SE = 0.165, p = 0.028; putamen, estimate = 0.396, SE = 0.137, p = 0.016).ConclusionsOur results suggest that genetic factors for PD risk may have heterogeneous effects on striatal dopaminergic degeneration, and some factors may be associated with a slower decline of dopaminergic activity. Composition of PD progression–specific GRS may be useful in predicting disease progression in patients.

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. © 2019

Aclidinium bromide is an inhaled long-acting muscarinic antagonist (LAMA). Although the initial potential increased cardiovascular and mortality risk among users of tiotropium has been ruled out by several observational studies, and clinical trials, there are still concerns related to the use of newer LAMA medications. The current study aimed to evaluate the risk of death among users of aclidinium and other LAMAs.We conducted a cohort and nested case-control study among patients with COPD aged 40 years or older to compare the risk of all-cause mortality among users of aclidinium and other COPD medications with the risk among users of long-acting β2 agonists (LABA), in the Clinical Practice Research Datalink (CPRD) in the United Kingdom (2012-2017).Mortality rates per 1,000 person-years were 32.9 for aclidinium, 43.8 for tiotropium, 38.0 for other LAMA, 47.1 for LABA/ICS, and 38.1 for LABA. The RR of death compared with current use of LABA was 0.54 (confidence interval [95% CI], 0.40-0.72) for aclidinium, 0.96 (95% CI, 0.76-1.21) for tiotropium, 0.76 (95% CI, 0.58-0.99) for other LAMA, and 1.08 (95% CI, 0.90-1.31) for LABA/ICS. Decreased risk for death observed among users of aclidinium was driven by overall current single use (RR = 0.41; 95% CI, 0.22-0.79), which corresponded to 26% of the aclidinium users (15 cases) and not by multiple use (RR = 1.02; 95% CI, 0.71-1.48).Use of aclidinium, tiotropium, other LAMA, or LABA/ICS was not associated with an increased risk of all-cause mortality as compared with the use of LABAs.

Early warning systems for monitoring toxic events may benefit from the availability of monoclonal antibodies enabling the sensitive and specific detection of anatoxin-a, a cyanotoxin involved in numerous cases of animal poisoning resulting from toxic algal blooms in freshwaters. Through the synthesis of three functionalized derivatives of anatoxin-a, we have succeeded in generating the first-ever reported immunoreagents (bioconjugates and antibodies) suitable for the development of immunoanalytical approaches aimed at rapid and onsite detection of this harmful cyanotoxin.