Bidirectional regulation of levodopa-induced dyskinesia by a specific neural ensemble in globus pallidus external segment.

Levodopa-induced dyskinesia (LID) is an intractable motor complication arising in Parkinson's disease with the progression of disease and chronic treatment of levodopa. However, the specific cell assemblies mediating dyskinesia have not been fully elucidated. Here, we utilize the activity-dependent tool to identify three brain regions (globus pallidus external segment [GPe], parafascicular thalamic nucleus, and subthalamic nucleus) that specifically contain dyskinesia-activated ensembles. An intensity-dependent hyperactivity in the dyskinesia-activated subpopulation in GPe (GPeTRAPed in LID) is observed during dyskinesia. Optogenetic inhibition of GPeTRAPed in LID significantly ameliorates LID, whereas reactivation of GPeTRAPed in LID evokes dyskinetic behavior in the levodopa-off state. Simultaneous chemogenetic reactivation of GPeTRAPed in LID and another previously reported ensemble in striatum fully reproduces the dyskinesia induced by high-dose levodopa. Finally, we characterize GPeTRAPed in LID as a subset of prototypic neurons in GPe. These findings provide theoretical foundations for precision medication and modulation of LID in the future.

Clinical features, disease progression, and nuclear imaging in ATXN2-related parkinsonism in a longitudinal cohort.

BACKGROUND: Spinocerebellar ataxia 2 (SCA2) with a low range of CAG repeat expansion of ATXN2 gene can present with predominant or isolated parkinsonism that closely resembles Parkinson's disease (PD). This study is aimed at comparing clinical features, disease progression, and nuclear imaging between ATXN2-related parkinsonism (ATXN2-P) and PD. METHODS: Three hundred and seventy-seven clinically diagnosed PD with family history were screened by multiplex ligation-dependent probe amplification, whole-exome sequencing or target sequencing, and dynamic mutation testing of 10 SCA subtypes. The baseline and longitudinal clinical features as well as the dual-tracer positron emission tomography (PET) imaging were compared between ATXN2-P and genetically undefined familial PD (GU-fPD). RESULTS: Fifteen ATXN2-P patients from 7 families and 50 randomly selected GU-fPD patients were evaluated. Significantly less resting tremor and more symmetric signs were observed in ATXN2-P than GU-fPD. No significant difference was found in motor progression and duration from onset to occurrence of fluctuation, dyskinesia, and recurrent falls between the two groups. Cognitive impairment and rapid-eye-movement sleep behavior disorder were more common in ATXN2-P. During follow-up, olfaction was relatively spared, and no obvious progression of cognition dysfunction evaluated by Mini-Mental State Examination scores was found in ATXN2-P. PET results of ATXN2-P demonstrated a symmetric, diffuse, and homogenous dopamine transporter loss of bilateral striatum and a glucose metabolism pattern inconsistent with that in PD. CONCLUSIONS: Symmetric motor signs and unique nuclear imaging might be the clues to distinguish ATXN2-P from GU-fPD.

A model incorporating clinicopathologic and liver imaging reporting and data system-based magnetic resonance imaging features to identify hepatocellular carcinoma in LR-M observations.

PURPOSE: To evaluate the predictive value of a combination model of Liver Imaging Reporting and Data System (LI-RADS)-based magnetic resonance imaging (MRI) and clinicopathologic features to identify atypical hepatocellular carcinoma (HCC) in LI-RADS category M (LR-M) observations. METHODS: A total of 105 patients with HCC based on surgery or biopsy who underwent preoperative MRI were retrospectively reviewed in the training group from hospital-1 between December 2016 and November 2020. The LI-RADS-based MRI features and clinicopathologic data were compared between LR-M HCC and non-HCC groups. Univariate and least absolute shrinkage and selection operator regression analyses were used to select the features. Binary logistic regression analysis was then conducted to estimate potential predictors of atypical HCC. A predictive nomogram was established based on the combination of MRI and clinicopathologic features and further validated using an independent external set of data from hospital-2. RESULTS: Of 113 observations from 105 patients (mean age, 61 years; 77 men) in the training set, 47 (41.59%) were classified as LR-M HCC. Following multivariate analysis, aspartate aminotransferase >40 U/L [odds ratio (OR): 4.65], alpha-fetoprotein >20 ng/mL (OR: 13.04), surface retraction (OR: 0.16), enhancing capsule (OR: 5.24), blood products in mass (OR: 8.2), and iso/hypoenhancement on delayed phase (OR: 10.26) were found to be independently correlated with LR-M HCC. The corresponding area under the curve for a combined model-based nomogram was 0.95 in the training patients (n = 113) and 0.90 in the validation cohort (n = 53). CONCLUSION: The combined model incorporating clinicopathologic and MRI features demonstrated a satisfactory prediction result for LR-M HCC.

A L-glutamine binding protein modified MNM structured optical fiber biosensor based on surface plasmon resonance sensing for detection of L-glutamine metabolism in vitro embryo culture.

A surface plasmon resonance (SPR) optical fiber sensor with multimode-coreless-multimode (MNM) structure was developed, which modified by L-glutamine-binding protein (QBP) for detection of L-glutamine (Gln). The QBP was immobilized on the surface of gold films by chemical cross-linking and exhibited a binding affinity for L-glutamine. The conformation of QBP can be changed from the "open" to the "closed", which led to a red-shift of the SPR peak when QBP bounded to L-glutamine. There was a good linear correlation between is a dependence of the SPR peak on and the concentration of L-glutamine concentration in the range 10-100 µM, with a sensitivity of 10.797nm/log10[Gln] for L-glutamine in the in vitro embryo culture (IVC) medium environment, and the limit of detection (LOD) is 1.187 µM. This QBP-modified MNM structure optical fiber SPR sensor provides a new idea for the developmental potential assessment of embryos in the process of in vitro embryo culture.

Extraction, characterization and anti-oxidant activity of polysaccharide from red Panax ginseng and Ophiopogon japonicus waste.

Red ginseng and Ophiopogon japonicus are both traditional Chinese medicines. They have also been used as food in China for thousands of years. These two herbs were frequently used in many traditional Chinese patent medicines. However, the carbohydrate compositions of these two herbs were not normally used during the production of said medicine, such as Shenmai injection, resulting in a large amount of waste composed of carbohydrates. In this study, the extraction conditions were optimized by response surface methodology. The Shenmai injection waste polysaccharide was extracted by using distilled water that was boiled under the optimized conditions. The Shenmai injection waste polysaccharide (SMP) was thereby obtained. SMP was further purified by anion exchange chromatography and gel filtration. With this method, a neutral polysaccharide fraction (SMP-NP) and an acidic polysaccharide fraction (SMP-AP) were obtained. The results of structure elucidation indicated that SMP-NP was a type of levan, and SMP-AP was a typical acidic polysaccharide. SMP-NP exhibited potential stimulation activity on the proliferation of five different Lactobacilli strains. Therefore, SMP-AP could promote the antioxidant defense of IPEC-J2 cells. These findings suggest that Shenmai injection waste could be used as a resource for prebiotics and antioxidants.

The genetic spectrum of a cohort of patients clinically diagnosed as Parkinson's disease in mainland China.

So far, over 20 causative genes of monogenic Parkinson's disease (PD) have been identified. Some causative genes of non-parkinsonian entities may also manifest with parkinsonism mimicking PD. This study aimed to investigate the genetic characteristics of clinically diagnosed PD with early onset age or family history. A total of 832 patients initially diagnosed with PD were enrolled, of which, 636 were classified into the early-onset group and 196 were classified into the familial late-onset group. The genetic testing included the multiplex ligation-dependent probe amplification and next generation sequencing (target sequencing or whole-exome sequencing). The dynamic variants of spinocerebellar ataxia were tested in probands with family history. In the early-onset group, 30.03% of patients (191/636) harbored pathogenic/likely pathogenic (P/LP) variants in known PD-related genes (CHCHD2, DJ-1, GBA (heterozygous), LRRK2, PINK1, PRKN, PLA2G6, SNCA and VPS35). Variants in PRKN were the most prevalent, accounting for 15.72% of the early-onset patients, followed by GBA (10.22%), and PLA2G6 (1.89%). And 2.52% (16/636) had P/LP variants in causative genes of other diseases (ATXN3, ATXN2, GCH1, TH, MAPT, GBA (homozygous)). In the familial late-onset group, 8.67% of patients (17/196) carried P/LP variants in known PD-related genes (GBA (heterozygous), HTRA2, SNCA) and 2.04% (4/196) had P/LP variants in other genes (ATXN2, PSEN1, DCTN1). Heterozygous GBA variants (7.14%) were the most common genetic cause found in familial late-onset patients. Genetic testing is of vital importance in differential diagnosis especially in early-onset and familial PD. Our findings may also provide some clues to the nomenclature of genetic movement disorders.

Dopaminergic Dysfunction and Glucose Metabolism Characteristics in Parkin-Induced Early-Onset Parkinson's Disease Compared to Genetically Undetermined Early-Onset Parkinson's Disease.

While early-onset Parkinson's disease (EOPD) caused by mutations in the parkin gene (PRKN) tends to have a relatively benign course compared to genetically undetermined (GU)-EOPD, the exact underlying mechanisms remain elusive. We aimed to search for the differences between PRKN-EOPD and GU-EOPD by dopamine transporter (DAT) and glucose metabolism positron-emission-tomography (PET) imaging. Twelve patients with PRKN-EOPD and 16 with GU-EOPD who accepted both 11C-2b-carbomethoxy-3b-(4-trimethylstannylphenyl) tropane (11C-CFT) and 18F-fluorodeoxyglucose PET were enrolled. The 11C-CFT uptake was analyzed on both regional and voxel levels, whereas glucose metabolism was assessed in a voxel-wise fashion. Correlations between DAT and glucose metabolism imaging, DAT imaging and clinical severity, as well as glucose metabolism imaging and clinical severity were explored. Both clinical symptoms and DAT-binding patterns in the posterior putamen were highly symmetrical in patients with PRKN-EOPD, and dopaminergic dysfunction in the ipsilateral putamen was severer in patients with PRKN-EOPD than GU-EOPD. Meanwhile, the DAT binding was associated with the severity of motor dysfunction in  patients with GU-EOPD only. Patients with PRKN-EOPD showed increased glucose metabolism in the contralateral medial frontal gyrus (supplementary motor area (SMA)), contralateral substantia nigra, contralateral thalamus, and contralateral cerebellum. Notably, glucose metabolic activity in the contralateral medial frontal gyrus was inversely associated with regional DAT binding in the bilateral putamen. Patients with PRKN-EOPD showed enhanced metabolic connectivity within the bilateral putamen, ipsilateral paracentral and precentral lobules, and the ipsilateral SMA. Collectively, compared to GU-EOPD, PRKN-EOPD is characterized by symmetrical, more severe dopaminergic dysfunction and relative increased glucose metabolism. Meanwhile, SMA with elevated glucose metabolism and enhanced connectivity may act as compensatory mechanisms in PRKN-EOPD. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-022-00077-8.

Explaining the resistomes in a megacity's water supply catchment: Roles of microbial assembly-dominant taxa, niched environments and pathogenic bacteria.

Antibiotic resistance genes (ARGs) in drinking water sources suggest the possible presence of resistant microorganisms that jeopardize human health. However, explanations for the presence of specific ARGs in situ are largely unknown, especially how their prevalence is affected by local microbial ecology, taxa assembly and community-wide gene transfer. Here, we characterized resistomes and bacterial communities in the Taipu River catchment, which feeds a key drinking water reservoir to a global megacity, Shanghai. Overall, ARG abundances decreased significantly as the river flowed downstream towards the reservoir (P < 0.01), whereas the waterborne bacteria assembled deterministically (|ßNRI| > 2.0) as a function of temperature and dissolved oxygen conditions with the assembly-dominant taxa (e.g. Ilumatobacteraceae and Cyanobiaceae) defining local resistomes (P < 0.01, Cohen's D = 4.22). Bacterial hosts of intragenomic ARGs stayed at the same level across the catchment (60 ∼ 70 genome copies per million reads). Among them, the putative resistant pathogens (e.g. Burkholderiaceae) carried mixtures of ARGs that exhibited high transmission probability (transfer counts = 126, P < 0.001), especially with the microbial assembly-dominant taxa. These putative resistant pathogens had densities ranging form 3.0 to 4.0 × 106 cell/L, which was more pronouncedly affected by resistome and microbial assembly structures than environmental factors (SEM, std-coeff ß = 0.62 vs. 0.12). This work shows that microbial assembly and resistant pathogens play predominant roles in prevelance and dissemination of resistomes in receiving water, which deserves greater attention in devisng control strategies for reducing in-situ ARGs and resistant strains in a catchment.

Global airborne bacterial community-interactions with Earth's microbiomes and anthropogenic activities.

Airborne bacteria are an influential component of the Earth's microbiomes, but their community structure and biogeographic distribution patterns have yet to be understood. We analyzed the bacterial communities of 370 air particulate samples collected from 63 sites around the world and constructed an airborne bacterial reference catalog with more than 27 million nonredundant 16S ribosomal RNA (rRNA) gene sequences. We present their biogeographic pattern and decipher the interlacing of the microbiome co-occurrence network with surface environments of the Earth. While the total abundance of global airborne bacteria in the troposphere (1.72 × 1024 cells) is 1 to 3 orders of magnitude lower than that of other habitats, the number of bacterial taxa (i.e., richness) in the atmosphere (4.71 × 108 to 3.08 × 109) is comparable to that in the hydrosphere, and its maximum occurs in midlatitude regions, as is also observed in other ecosystems. The airborne bacterial community harbors a unique set of dominant taxa (24 species); however, its structure appears to be more easily perturbed, due to the more prominent role of stochastic processes in shaping community assembly. This is corroborated by the major contribution of surface microbiomes to airborne bacteria (averaging 46.3%), while atmospheric conditions such as meteorological factors and air quality also play a role. Particularly in urban areas, human impacts weaken the relative importance of plant sources of airborne bacteria and elevate the occurrence of potential pathogens from anthropogenic sources. These findings serve as a key reference for predicting planetary microbiome responses and the health impacts of inhalable microbiomes with future changes in the environment.

Inhalable antibiotic resistomes emitted from hospitals: metagenomic insights into bacterial hosts, clinical relevance, and environmental risks.

BACKGROUND: Threats of antimicrobial resistance (AMR) to human health are on the rise worldwide. Airborne fine particulate matter (PM2.5), especially those emitted from hospitals, could serve as a substantial yet lesser-known environmental medium of inhalable antibiotic resistomes. A genome-centric understanding of the hosting bacterial taxa, mobility potential, and consequent risks of the resistomes is needed to reveal the health relevance of PM2.5-associated AMR from clinical settings. RESULTS: Compared to urban ambient air PM2.5, the hospital samples harbored nearly twice the abundance of antibiotic resistantance genes (ARGs, ~ 0.2 log10(ARGs/16S rRNA gene)) in the summer and winter sampled. The profiled resistome was closely correlated with the human-source-influenced (~ 30% of the contribution) bacterial community (Procrustes test, P < 0.001), reflecting the potential antibiotic-resistant bacteria (PARB), such as the human commensals Staphylococcus spp. and Corynebacterium spp. Despite the reduced abundance and diversity of the assembled metagenomes from summer to winter, the high horizontal transfer potential of ARGs, such as the clinically relevant blaOXA and bacA, in the human virulent PARB remained unaffected in the hospital air PM samples. The occurring patterns of ß-lactam resistance genes and their hosting genomes in the studied hospital-emitting PM2.5 were closely related to the in-ward ß-lactam-resistant infections (SEM, std = 0.62, P < 0.01). Featured with more abundant potentially virulent PARB (2.89 genome copies/m3-air), the hospital samples had significantly higher resistome risk index scores than the urban ambient air samples, indicating that daily human exposure to virulent PARB via the inhalation of PM2.5 was ten times greater than from the ingestion of drinking water. CONCLUSIONS: The significance of AMR in the studied hospital-emitting PM2.5 was highlighted by the greater abundance of ARGs, the prevalence of potentially virulent PARB, and the close association with hospital in-ward ß-lactam infections. A larger-scale multi-source comparison of genome-resolved antibiotic resistomes is needed to provide a more holistic understanding to evaluate the importance of airborne AMR from the "One-Health" perspective. Video Abstract.

In Vivo 18 F-APN-1607 Tau Positron Emission Tomography Imaging in MAPT Mutations: Cross-Sectional and Longitudinal Findings.

BACKGROUND: Frontotemporal lobar degeneration with tauopathy caused by MAPT (microtubule-associated protein tau) mutations is a highly heterogenous disorder. The ability to visualize and longitudinally monitor tau deposits may be beneficial to understand disease pathophysiology and predict clinical trajectories. OBJECTIVE: The aim of this study was to investigate the cross-sectional and longitudinal 18 F-APN-1607 positron emission tomography/computed tomography (PET/CT) imaging findings in MAPT mutation carriers. METHODS: Seven carriers of MAPT mutations (six within exon 10 and one outside of exon 10) and 15 healthy control subjects were included. All participants underwent 18 F-APN-1607 PET/CT at baseline. Three carriers of exon 10 mutations received follow-up 18 F-APN-1607 PET/CT scans. Standardized uptake value ratio (SUVR) maps were obtained using the cerebellar gray matter as the reference region. SUVR values observed in MAPT mutation carriers were normalized to data from healthy control subjects. A regional SUVR z score ≥ 2 was used as the criterion to define positive 18 F-APN-1607 PET/CT findings. RESULTS: Although the seven study patients had heterogenous clinical phenotypes, all showed a significant 18 F-APN-1607 uptake characterized by high-contrast signals. However, the anatomical localization of tau deposits differed in patients with distinct clinical symptoms. Follow-up imaging data, which were available for three patients, demonstrated worsening trends in patterns of tau accumulation over time, which were paralleled by a significant clinical deterioration. CONCLUSIONS: Our data represent a promising step in understanding the usefulness of 18 F-APN-1607 PET/CT imaging for detecting tau accumulation in MAPT mutation carriers. Our preliminary follow-up data also suggest the potential value of 18 F-APN-1607 PET/CT for monitoring the longitudinal trajectories of frontotemporal lobar degeneration caused by MAPT mutations. © 2021 International Parkinson and Movement Disorder Society.

Determinants of quality of life in Parkinson's disease: a perspective of novel clinical subtypes.

OBJECTIVE: New subtyping classification systems of Parkinson's disease (PD) have been proposed for phenotyping patients into three different subtypes: mild motor-predominant (PD-MMP), intermediate (PD-IM) and diffuse malignant (PD-DM). The quality of life (QoL) underlying the novel PD clinical subtypes is unknown. This study aimed explore the feasibility of the classification in Chinese PD patients and to investigate the potential heterogeneous determinants of QoL among the three subtypes. METHODS: 298 PD patients were enrolled, including 129 PD-MMP patients, 121 PD-IM patients and 48 PD-DM patients. All patients completed the QoL assessment, clinical evaluations and neuropsychological tests. Univariate linear analysis and multiple stepwise regression analysis were performed to identify determinants of QoL. RESULTS: Compared to PD-MMP patients, PD-IM and PD-DM patients had more impaired QoL. The Geriatric Depression Rating Scale (GDS) score, Non-Motor Symptoms Questionnaire (NMSQ) score, Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score and Epworth Sleepiness Score (ESS) were independent contributors to QoL in PD-MMP patients. The GDS score, ESS and sniffin' sticks screening 12 test score were independent contributors to QoL in PD-IM patients. The GDS score and Mini Mental State Examination score were independent contributors to QoL in PD-DM patients. INTERPRETATION: The new novel subtyping classification is feasible for Chinese PD patients. Although depression was the most crucial determinant for QoL in PD-MMP, PD-IM and PD-DM patients, the other contributors of QoL in the three subtypes were heterogeneous. These findings may prompt clinicians to target specific factors for improving QoL depending on PD subtypes.

Exogenous Expression of pou5f3 Facilitates the Development of Somatic Cell Nuclear Transfer Embryos in Zebrafish at the Early Stage.

Enucleated oocytes can reprogram differentiated nuclei to totipotency after somatic cell nuclear transfer (SCNT), which is valuable in understanding nuclear reprogramming and generating genetically modified animals. To date, reprogramming efficiency is low and the development of SCNT embryos is not going as well as anticipated. To further disclose the reprogramming mechanisms during SCNT zebrafish embryo development, we examined the expression patterns of transcription regulation factors and regulated them by mRNA and morpholino microinjection. In this study, we show that stem cell-related transcription factors are downregulated in zebrafish SCNT embryos at the blastula stage. Exogenous expression of pou5f3 at the single-cell stage improves SCNT embryo development from the blastula to the gastrula stage. We also found that exogenous expression of klf4 or sox2 decreases SCNT embryo development from the blastula to the gastrula stage, while expression of nanog is necessary for the development of SCNT embryos. Our results conclude that zebrafish pou5f3 facilitates the development of SCNT embryos from the blastula to gastrula stage.

Cerebral Metabolism Related to Cognitive Impairments in Multiple System Atrophy.

Objective: We aimed to characterize the cognitive profiles in multiple system atrophy (MSA) and explore the cerebral metabolism related to the cognitive decline in MSA using 18F-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET). Methods: In this study, 105 MSA patients were included for cognitive assessment and 84 of them were enrolled for 18F-FDG PET analysis. The comprehensive neuropsychological tests covered five main domains including execution, attention, memory, language, and visuospatial function. The cognitive statuses were classified to MSA with normal cognition (MSA-NC) and MSA with cognitive impairment (MSA-CI), including dementia (MSA-D), and mild cognitive impairment (MSA-MCI). With 18F-FDG PET imaging, the cerebral metabolism differences among different cognitive statuses were analyzed using statistical parametric mapping and post-hoc analysis. Results: Among 84 MSA patients, 52 patients were found with MSA-CI, including 36 patients as MSA-MCI and 16 patients as MSA-D. In detail, the cognitive impairments were observed in all the five domains, primarily in attention, executive function and memory. In 18F-FDG PET imaging, MSA-D and MSA-MCI patients exhibited hypometabolism in left middle and superior frontal lobe compared with MSA-NC (p < 0.001). The normalized regional cerebral metabolic rate of glucose (rCMRglc) in left middle frontal lobe showed relative accuracy in discriminating MSA-CI and MSA-NC [areas under the curve (AUC) = 0.750; 95%CI = 0.6391-0.8609]. Conclusions: Cognitive impairments were not rare in MSA, and the hypometabolism in frontal lobe may contribute to such impairments.

WWP2 and PPP1R3A are abnormally regulated in arrhythmia-induced cardiac damage.

The present work aimed to identify the roles of WWP2 (an E3 ubiquitin-protein ligase) and protein phosphatase 1 regulatory subunit 3A (PPP1R3A) in different pathological stages of cardiac arrhythmia development. Leptin-deficient mice (C57BLKS-Leprdb/Leprdb) were used for the development of initial and severe stages of cardiac arrhythmia. Histology, ECG, immunohistochemistry and Western blotting were used to analyse cardiac arrhythmia, WWP2 and PPP1R3A expression. Histopathological studies of 4-month-old mice showed cardiac degeneration, cellular lesions, and swollen tissue structure with loss of tissue elasticity, indicative of the initial condition of cardiac arrhythmia. The leptin-deficient 7-month-old mice showed cardiac tissue hardening with increased secretion of extracellular matrix. The development of initial- and severe-cardiac arrhythmia was further evident with electrocardiogram studies, which showed more PP interval variations as the disease progressed. At the molecular level, WWP2 showed marginal upregulation in the initial stages of arrhythmia and was predominantly expressed within nuclei. WWP2 was overexpressed 6.6-fold in the severe stage of cardiac arrhythmia and was spread throughout the tissue layer. Interestingly, PPP1R3A was significantly overexpressed in initial cardiac arrhythmia conditions, but was downregulated and restricted to more nuclear expression in advanced cardiac arrhythmia. Silencing of PPP1R3A, enhances the expression of WWP2 to 5.3-fold in initial stages, but remarkable variation not observed in advanced cardiac arrhythmia conditions. Our results suggest that PPP1R3A had a control over WWP2 in the initial stages of cardiac arrhythmia. In particular, PPP1R3A overexpression implies its potential protective effect in initial cardiac arrhythmia stages.

Dopaminergic and Metabolic Correlations With Cognitive Domains in Non-demented Parkinson's Disease.

BACKGROUND: Accruing positron emission tomography (PET) studies have suggested that dopaminergic functioning and metabolic changes are correlated with cognitive dysfunction in Parkinson's disease (PD). Yet, the relationship between dopaminergic or cerebral metabolism and different cognitive domains in PD is poorly understood. To address this scarcity, we aimed to investigate the interactions among dopaminergic bindings, metabolic network changes, and the cognitive domains in PD patients. METHODS: We recruited 41 PD patients, including PD patients with no cognitive impairment (PD-NC; n = 21) and those with mild cognitive impairment (PD-MCI; n = 20). All patients underwent clinical evaluations and a schedule of neuropsychological tests and underwent both 11C-N-2-carbomethoxy-3-(4-fluorophenyl)-tropane (11C-CFT) and 18F-fluorodeoxyglucose (18F-FDG) PET imaging. RESULTS: 11C-CFT imaging revealed a significant positive correlation between executive function and striatal dopamine transporter (DAT) binding at both the voxel and regional levels. Metabolic imaging revealed that executive function correlated with 18F-FDG uptake, mainly in inferior frontal gyrus, putamen, and insula. Further analysis indicated that striatal DAT binding correlated strictly with metabolic activity in the temporal gyrus, medial frontal gyrus, and cingulate gyrus. CONCLUSION: Our findings might promote the understanding of the neurobiological mechanisms underlying cognitive impairment in PD.

Disease Progression in Patients with Parkin-Related Parkinson's Disease in a Longitudinal Cohort.

BACKGROUND: There was a paucity of follow-up studies in the disease progression of early-onset PD patients with Parkin mutations (Parkin-EOPD). Here we conducted a longitudinal study to investigate the progression of motor and cognitive features of Parkin-EOPD patients. METHODS: Genetic analysis was performed via target sequencing and multiplex ligation-dependent probe amplification. Thirty patients carrying homozygous or compound heterozygous Parkin mutations with at least 2 follow-up revisions were investigated as the Parkin-EOPD group. Fifty-two patients with at least 2 follow-up revisions, who did not have any known causative PD mutations, GBA or LRRK2 risk variants, a heterozygous Parkin mutation or 2 Parkin mutations without a segregation test, were defined as the genetically undefined EOPD (GU-EOPD) group. A linear mixed-effect model was implemented to evaluate longitudinal changes in motor symptoms and cognition. RESULTS: At baseline, the Parkin-EOPD group had a lower Unified Parkinson's Disease Rating Scale score (UPDRS-III) (off-medication) than the GU-EOPD group, without significant differences in cognition. A longitudinal study showed the estimated progression rate per year (standard error) of the UPDRS-III score (off-medication) was lower in the Parkin-EOPD group (0.203 [0.3162] points per year) than in the GU-EOPD group (1.056 [0.3001] points per year). The difference in the UPDRS-III score rate between the 2 groups was 0.853 (0.4183) (P = 0.042). The Parkin-EOPD group showed better maintenance of spatial processing ability compared with the GU-EOPD group (P = 0.027). CONCLUSION: Parkin-EOPD patients showed a slower deterioration of motor symptoms and a better spatial processing ability than GU-EOPD patients, which suggests that subtyping according to genetic features can help predict PD progression. © 2020 International Parkinson and Movement Disorder Society.

Propagated α-synucleinopathy recapitulates REM sleep behaviour disorder followed by parkinsonian phenotypes in mice.

Idiopathic rapid eye movement sleep behaviour disorder (RBD) is now recognized as an early manifestation of α-synucleinopathies. Increasing experimental studies demonstrate that manipulative lesion or inactivation of the neurons within the sublaterodorsal tegmental nucleus (also known as the subcoeruleus nucleus in humans) can induce RBD-like behaviours in animals. As current RBD animal models are not established on the basis of α-synucleinopathy, they do not represent the pathological substrate of idiopathic RBD and thus cannot model the phenoconversion to Parkinson's disease. The purpose of this study was therefore to establish an α-synucleinopathy-based RBD animal model with the potential to convert to parkinsonian disorder. To this end, we first determined the functional neuroanatomical location of the sublaterodorsal tegmental nucleus in wild-type C57BL/6J mice and then validated its function by recapitulating RBD-like behaviours based on this determined nucleus. Next, we injected preformed α-synuclein fibrils into the sublaterodorsal tegmental nucleus and performed regular polysomnographic recordings and parkinsonian behavioural and histopathological studies in these mice. As a result, we recapitulated RBD-like behaviours in the mice and further showed that the α-synucleinopathy and neuron degeneration identified within the sublaterodorsal tegmental nucleus acted as the neuropathological substrates. Subsequent parkinsonian behavioural studies indicated that the α-synucleinopathy-based RBD mouse model were not stationary, but could further progress to display parkinsonian locomotor dysfunction, depression-like disorder, olfactory dysfunction and gastrointestinal dysmotility. Corresponding to that, we determined α-synuclein pathology in the substantia nigra pars compacta, olfactory bulb, enteral neuroplexus and dorsal motor nucleus of vagus nerve, which could underlie the parkinsonian manifestations in mice. In conclusion, we established a novel α-synucleinopathy-based RBD mouse model and further demonstrated the phenoconversion of RBD to Parkinson's disease in this animal model.