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Radioactive nuclei with lifetimes on the order of millions of years can reveal the formation history of the Sun and active nucleosynthesis occurring at the time and place of its birth 1,2 . Among such nuclei whose decay signatures are found in the oldest meteorites, 205 Pb is a powerful example, as it is produced exclusively by slow neutron captures (the s process), with most being synthesized in asymptotic giant branch (AGB) stars 3-5 . However, making accurate abundance predictions for 205 Pb has so far been impossible because the weak decay rates of 205 Pb and 205 Tl are very uncertain at stellar temperatures 6,7 . To constrain these decay rates, we measured for the first time the bound-state β - decay of fully ionized 205 Tl 81+ , an exotic decay mode that only occurs in highly charged ions. The measured half-life is 4.7 times longer than the previous theoretical estimate 8 and our 10% experimental uncertainty has eliminated the main nuclear-physics limitation. With new, experimentally backed decay rates, we used AGB stellar models to calculate 205 Pb yields. Propagating those yields with basic galactic chemical evolution (GCE) and comparing with the 205 Pb/ 204 Pb ratio from meteorites 9-11 , we determined the isolation time of solar material inside its parent molecular cloud. We find positive isolation times that are consistent with the other s-process short-lived radioactive nuclei found in the early Solar System. Our results reaffirm the site of the Sun's birth as a long-lived, giant molecular cloud and support the use of the 205 Pb- 205 Tl decay system as a chronometer in the early Solar System., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Levodopa (L-dopa) therapy is the most effective pharmacological treatment for motor symptoms of Parkinson's disease (PD). However, its effect on brain functional network dynamics is still unclear. Here, we recruited 26 PD patients and 24 healthy controls, and acquired their resting-state functional MRI data before (PD-OFF) and after (PD-ON) receiving 400 mg L-dopa. Using the independent component analysis and the sliding-window approach, we estimated the dynamic functional connectivity (dFC) and examined the effect of L-dopa on the temporal properties of dFC states, the variability of dFC and functional network topological organization. We found that PD-ON showed decreased mean dwell time in sparsely connected State 2 than PD-OFF, the transformation of the dFC state is more frequent and the variability of dFC was decreased within the auditory network and sensorimotor network in PD-ON. Our findings provide new insights to understand the dynamic neural activity induced by L-dopa therapy in PD patients., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests., (Copyright © 2024. Published by Elsevier Inc.)

Nitrogen (N) is of great significance to the absorption, distribution and detoxification of cadmium (Cd). Ectomycorrhizal fungi (EMF) are able to affect the key processes of plant N uptake to resist Cd stress, while the mechanism is still unclear. Therefore, we explored potential strategies of Cenococcum geophilum (C. geophilum) symbiosis to alleviate Cd stress in Pinus massoniana (P. massoniana) from the perspective of plant N metabolism and soil N transformation. The results showed that inoculation of C. geophilum significantly increased the activities of NR, NiR and GS in the shoots and roots of P. massoniana, thereby promoting the assimilation of NO 3 - and NH 4 + into amino acids. Moreover, C. geophilum promoted soil urease and protease activities, but decreased soil NH 4 + content, indicating that C. geophilum might increase plant uptake of soil inorganic N. qRT-PCR results showed that C3 symbiosis significantly up-regulated the expression of genes encoding functions involved in NH 4 + uptake (AMT3;1), NO 3 - uptake (NRT2.1, NRT2.4, NRT2.9), as well as Cd resistance (ABCC1 and ABCC2), meanwhile down-regulated the expression of NRT7.3, Cd transporter genes (HMA2 and NRAMP3) in the roots of P. massoniana seedlings. These results demonstrated that C. geophilum was able to alleviate Cd stress by increasing the absorption and assimilation of inorganic N in plants and inhibiting the transport of Cd from roots to shoots, which provided new insights into how EMF improved host resistance to abiotic stress., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

JOURNAL/nrgr/04.03/01300535-202501000-00031/figure1/v/2024-05-14T021156Z/r/image-tiff Early identification and treatment of stroke can greatly improve patient outcomes and quality of life. Although clinical tests such as the Cincinnati Pre-hospital Stroke Scale (CPSS) and the Face Arm Speech Test (FAST) are commonly used for stroke screening, accurate administration is dependent on specialized training. In this study, we proposed a novel multimodal deep learning approach, based on the FAST, for assessing suspected stroke patients exhibiting symptoms such as limb weakness, facial paresis, and speech disorders in acute settings. We collected a dataset comprising videos and audio recordings of emergency room patients performing designated limb movements, facial expressions, and speech tests based on the FAST. We compared the constructed deep learning model, which was designed to process multi-modal datasets, with six prior models that achieved good action classification performance, including the I3D, SlowFast, X3D, TPN, TimeSformer, and MViT. We found that the findings of our deep learning model had a higher clinical value compared with the other approaches. Moreover, the multi-modal model outperformed its single-module variants, highlighting the benefit of utilizing multiple types of patient data, such as action videos and speech audio. These results indicate that a multi-modal deep learning model combined with the FAST could greatly improve the accuracy and sensitivity of early stroke identification of stroke, thus providing a practical and powerful tool for assessing stroke patients in an emergency clinical setting., (Copyright © 2025 Copyright: © 2025 Neural Regeneration Research.)

Background: Previous research revealed differences in cerebellar white matter integrity by disease stages, indicating a compensatory role in Parkinson's disease (PD). However, the temporal evolution of cerebellar white matter microstructure in patients with PD (PwPD) remains unclear., Objective: To unravel temporal evolution of cerebellar white matter and its dopaminergic correlates in PD., Methods: We recruited 124 PwPD from the PPMI study. The participants were divided into two subsets: Subset 1 (n = 41) had three MRI scans (baseline, 2 years, and 4 years), and Subset 2 (n = 106) had at least two MRI scans at baseline, 1 year, and/or 2 years. Free water-corrected diffusion metrics were used to measure the microstructural integrity in cerebellar peduncles (CP), the main white matter tracts connecting to and from the cerebellum. The ACAPULCO processing pipeline was used to assess cerebellar lobules volumes. Linear mixed-effect models were used to study longitudinal changes. We also examined the relationships between microstructural integrity in CP, striatal dopamine transporter specific binding ratio (SBR), and clinical symptoms., Results: Microstructural changes in CP showed a non-linear pattern in PwPD. Free water-corrected fractional anisotropy (FAt) increased in the first two years but declined from 2 to 4 years, while free water-corrected mean diffusivity exhibited the opposite trend. The initial increased FAt in CP correlated with cerebellar regional volume atrophy, striatal dopaminergic SBR decline, and worsening clinical symptoms, but this correlation varied across disease stages., Conclusions: Our findings suggest a non-linear evolution of microstructural integrity in CP throughout the course of PD, indicating the adaptive structural reorganization of the cerebellum simultaneously with progressive striatal dopaminergic degeneration in PD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: This study explored the influence of the life course on mental health by identifying key trends, seminal works, and themes in existing research. Additionally, it highlights the major discussions at the intersection of life course and mental health., Methods: Documents were extracted from the Web of Science Core Collection (WoSCC), to systematically analyze themes on mental health outcomes across the life course. The analysis was based on key bibliometric tools, including VOSviewer 1.6.11, R Studio software, and GraphPad Prism 9 to analyze the evolution and impact of scholarly contributions in this domain., Results: The accumulated body of research concerning the life course's impact on mental health, which began to emerge around 1990 displayed a consistently upward trend. Predominant contributions originate from developed nations and frequently look into the psychosocial determinants of mental health over life course. Life course and mental health studies have been extensively infused with biopsychosocial frameworks that consider the role of genetic makeup, neurodevelopment, cognition, affect, sociocultural dynamics, and interpersonal relationships. Life course theory application in mental health highlight the substantive effects of accumulated adversities, notably social determinants of health, adverse childhood experiences (ACEs), and their implications for subsequent mental health outcomes., Conclusion: The nexus of life course and mental health outcomes demands further scholarly interrogation, particularly within underserved regions, to strengthen protective mechanisms for vulnerable populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Shaojun, Akintunde, Okagbue, Isangha and Musa.)

Background: Sphingolipid dysregulation in Parkinson's disease (PD) may affect the release and uptake of striatal dopamine. However, the longitudinal relationship between sphingolipids, striatal dopaminergic degeneration, and clinical correlates in idiopathic PD (iPD) remain unclear., Objective: To investigate the relationship between plasma sphingolipids, striatal dopamine transporter specific binding ratio (DAT-SBR) and clinical symptoms in iPD., Methods: We included 283 iPD patients and 121 healthy controls (HC) from the Parkinson's Progression Markers Initiative (PPMI), utilizing available data on plasma sphingolipids (sphingomyelin [SM] and ceramide [CER]), striatal DAT-SBR and clinical assessments. Linear mixed models and mediation analyses were used to examine the relationship between sphingolipids, DAT-SBR, and clinical progression in iPD., Results: Lower baseline SM levels were significantly associated with a faster decline in DAT-SBR in both the caudate (p = 0.015) and putamen (p = 0.002), with the putamen association remaining significant after Bonferroni correction (p = 0.015). No significant association was found for CER. Patients in the lowest quartile of baseline SM showed faster progression in MDS-UPDRS I (p = 0.013) and II (p = 0.011), while those in the lowest quartile of baseline CER showed faster progression in MDS-UPDRS II (p = 0.013) and III (p = 0.033). The progression rate of caudate DAT-SBR partially mediated the relationships between SM and progression in MDS-UPDRS I and II (p < 0.01)., Conclusion: Sphingolipids are associated with worse dopaminergic degeneration and potentially linked to faster progression in iPD, holding the promise for identifying individuals with faster progression in iPD., Competing Interests: Declaration of competing interest The authors do not have any pertinent financial or non-financial conflicts of interest to report., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: Rare studies have investigated the association between heterogeneity of motor progression and risk of early cognitive impairment in Parkinson's disease (PD). In this study, we aim to identify distinct trajectories of motor progression longitudinally and investigate their impact on predicting mild cognitive impairment (MCI)., Methods: A 5-year cohort including 415 PD patients at baseline was collected from the Parkinson's Progression Markers Initiative. The severity of motor symptoms was evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale part III. The latent class trajectory model and nonlinear mixed-effects model were used to analyze and delineate the longitudinal changes in motor symptoms. Propensity score matching (PSM) was used to minimize the impact of potential confounders. Cox proportional hazard models were applied to calculate hazard ratios for MCI, and a Kaplan-Meier curve was generated using the occurrence of MCI during the follow-up as the time-to-event., Results: Two latent trajectories were identified: a mild and remitting motor symptoms class (Class 1, 33.01%) and a severe and progressive motor symptom class (Class 2, 66.99%). Patients in Class 2 initially exhibited severe motor symptoms that worsened progressively despite receiving anti-PD medications. In comparison, patients in Class 1 exhibited milder symptoms that improved following drug therapy and a slower progression. During a 5-year follow-up, patients in Class 2 showed a higher risk of developing MCI compared to those in Class 1 before PSM (Log-Rank 28.58, p < 0.001) and after PSM (Log-Rank 8.20, p = 0.004)., Conclusions: PD patients with severe and progressive motor symptoms are more likely to develop MCI than those with mild and stable motor symptoms., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Purpose: To investigate interocular asymmetry (IA) of retinal structure and vessel density in patients with Parkinson's disease (PD) and normal controls (NC)., Methods: Seventy-eight subjects including 40 PD patients and 38 NC had completed optical coherence tomography angiography (OCTA) and neurological examinations for three rating scales (UPDRS-III, MMSE and MoCA). The IA was calculated by the absolute value of difference in right and left eyes. The IA of thickness in macular ganglion cell inner-plexiform layer (GCIPL), peripapillary retinal nerve fiber layer (pRNFL), and vessel density of superficial capillary plexus (SCP), deep capillary plexus (DCP), radial peripapillary capillary (RPC) were obtained from OCTA., Results: The motor-symptom-onset side of eyes showed lower vessel density in parafovea of SCP (51.09 ± 3.46 vs 49.81 ± 4.16, P = 0.03) and superior hemi of perifovea DCP (49.55 ± 5.81 vs 47.33 ± 5.71, = 0.04). The PD patients showed larger IA in thickness of superior half of pRNFL (5.27 [2.67, 10.87] vs 3.08 [1.62, 5.61], P = 0.02) and parafovea GCIPL (2.40[1.25, 6.35] vs 1.40[0.50, 2.45], P = 0.02). No significant interocular asymmetry was found in vessel density between PD and NC. A higher UPDRS-III scale was associated with larger IA in GCIPL (β = 0.093, P = 0.001) and smaller IA in DCP (β = -0.065, P = 0.037)., Conclusion: The motor-symptom-onset side of eyes showed more severe loss of macular vessel density than the other side of eyes. The PD patients showed asymmetrical structural change in GCIPL and pRNFL, which showed the potential as the diagnostic biomarker for PD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Soot nanoparticles (SNPs) are black carbon prevalent in atmospheric environment with significant impacts on public health, leading to neurodegenerative diseases including development of Parkinson's disease (PD). This study investigated the effects of SNPs exposure on PD symptoms, employing both in vivo and in vitro PD models. In the in vivo experiments, animal behavior assessments showed that SNPs exposure exacerbated motor and cognitive impairments in PD mice. Molecular biology techniques further unveiled that SNPs aggravated degeneration of dopaminergic neurons. In vitro experiments revealed that SNPs exposure intensified ferroptosis of PD cells by increasing reactive oxygen species and iron ion levels, while reducing glutathione levels and mitochondrial membrane potential. Sequencing tests indicated elevated N6-methyladenosine (m6A) alteration of the ferroptosis-related protein, acyl-CoA synthetase long chain family member 4 (ACSL4). This study demonstrates that SNPs may exacerbate the onset and progression of PD by recruiting YTH domain-containing family protein 1 (YTHDF1) protein, enhancing m6A methylation in the ACSL4 5'UTR, amplifying ACSL4 protein expression, and accelerating the ferroptosis process in dopaminergic neurons. These molecular mechanisms underlying SNPs exacerbation of PD development may provide crucial insights for formulating environmental safety regulations and potential therapeutic strategies addressing PD in populations residing in regions with varied air quality., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

To investigate brain network centrality and connectivity alterations in different Parkinson's disease (PD) clinical subtypes using resting-state functional magnetic resonance imaging (RS-fMRI), and to explore the correlation between baseline connectivity changes and the clinical progression. Ninety-two PD patients were enrolled at baseline, alongside 38 age- and sex-matched healthy controls. Of these, 85 PD patients underwent longitudinal assessments with a mean of 2.75 ± 0.59 years. Two-step cluster analysis integrating comprehensive motor and non-motor manifestations was performed to define PD subtypes. Degree centrality (DC) and secondary seed-based functional connectivity (FC) were applied to identify brain network centrality and connectivity changes among groups. Regression analysis was used to explore the correlation between baseline connectivity changes and clinical progression. Cluster analysis identified two main PD subtypes: mild PD and moderate PD. Two different subtypes within the mild PD were further identified: mild motor-predominant PD and mild-diffuse PD. Accordingly, the disrupted DC and seed-based FC in the left inferior frontal orbital gyrus and left superior occipital gyrus were severe in moderate PD. The DC and seed-based FC alterations in the right gyrus rectus and right postcentral gyrus were more severe in mild-diffuse PD than in mild motor-predominant PD. Moreover, disrupted DC were associated with clinical manifestations at baseline in patients with PD and predicted motor aspects progression over time. Our study suggested that brain network centrality and connectivity changes were different among PD subtypes. RS-fMRI holds promise to provide an objective assessment of subtype-related connectivity changes and predict disease progression in PD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this study, a novel Fe 3 O 4 -based biochar coupled surface-imprinted polymer was constructed via simple hydrothermal route for salicylic acid recognition and degradation in advanced oxidation processes. The material exhibited excellent adsorption capability, up to 118.23 mg g -1 , and efficient degradation performance, 87.44% removal rate within 240 min, based on integrating the advantages of both huge specific surface area as well as abundant functional groups from biochars and specific recognition sites from imprinted cavities. Moreover, high selectivity coefficient (11.67) showed stable recognition in single and binary systems. SO 4 •- and • OH were confirmed as reactive oxygen species in catalytic reaction according to quenching experiments and EPR analysis. The degradation mechanism and pathway were unraveled by DFT calculations and LC-MS. Furthermore, the results of toxicity evaluation, stability and reusability demonstrated application potential in the field of water environment restoration. This study confirmed that molecular imprinting provided a promising solution to targeted removal of emerging environmental pollutants by degrading after the enrichment of pollutants to the composites surface., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Microglia-mediated neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Triggering receptor expressed on myeloid cells 2 (TREM2) confers strong neuroprotective effects in PD by regulating the phenotype of microglia. Recent studies suggest that TREM2 regulates high glucose-induced microglial inflammation through the NLRP3 signaling pathway. This study aimed to investigate the effect of TREM2 on NLRP3 inflammasome activation and neuroinflammation in PD. Mice were injected with AAV-TREM2-shRNA into both sides of the substantia nigra using a stereotactic injection method, followed by intraperitoneal injection of MPTP to establish chronic PD mouse model. Behavioral assessments including the pole test and rotarod test were conducted to evaluate the effects of TREM2 deficiency on MPTP-induced motor dysfunction. Immunohistochemistry of TREM2 and tyrosine hydroxylase (TH), immunohistochemistry and immunofluorescence Iba1, Western blot of NLRP3 inflammasome and its downstream inflammatory factors IL-1β and IL-18, and the key pyroptosis factors GSDMD and GSDMD-N were performed to explore the effect of TREM2 on NLRP3 inflammasome and neuroinflammation. In an in vitro experiment, lentivirus was used to interfere with the expression of TREM2 in BV2 microglia, and then lipopolysaccharide (LPS) and adenopterin nucleoside triphosphate (ATP) were used to stimulate inflammation to construct a cellular inflammation model. The expression differences of NLRP3 inflammasome and its components were detected by qPCR and Western blot. In vivo, TREM2 knockdown aggravated the loss of dopaminergic neuron and the decline of motor function. After TREM2 knockdown, the number of activated microglia was significantly increased, and the expression of cleaved caspase-1, NLRP3 inflammasome, IL-1β, GSDMD, and GSDMD-N was increased. In vitro, TREM2 knockdown aggravated the inflammatory response of BV2 cells stimulated by LPS and promoted the activation of NLRP3 inflammasome through the NF-κB pathway. In addition, TREM2 knockdown also promoted the expression of TLR4/MyD88, an upstream factor of the NF-κB pathway. Our vivo and vitro data showed that TREM2 knockdown promoted NLRP3 inflammasome activation and downstream inflammatory response, promoted pyroptosis, and aggravated dopaminergic neuron loss. TREM2 acts as an anti-inflammatory in PD through the TLR4/MyD88/NF-κB pathway, which extends previous findings and supports the notion that TREM2 ameliorates neuroinflammation in PD., (© 2023. The Author(s).)

Objective: This study aims to determine the link between choroid plexus (CP) volume and cognitive decline in patients with early-stage Parkinson's disease (PD) and to test whether pathological proteins in the cerebrospinal fluid (CSF) are involved in the modulation of any detrimental effects from CP volume., Methods: Data on 95 early-stage PD patients with 5 years of follow-up were collected from the Parkinson's Progression Marker Initiative cohort. The patients were separated into three groups based on tertiles of baseline CP volume. We then used a linear mixed model for longitudinal analysis and conducted path analysis to investigate mediating effects., Results: At baseline, the patients in both the upper and middle tertile group were older and had lower concentrations of CSF Aβ 1-42 than those in the lowest tertile group. Longitudinal analysis showed that the upper tertile group suffered from a more rapid cognitive decline in the Symbol Digit Modalities test, Hopkins Verbal Learning Test (HVLT)-retention, and HVLT delayed recalled score. Furthermore, path analysis showed that the pathological effects of CP volume on the 5-year decline in memory might be partly mediated by the CSF Aβ 1-42 /αsyn ratio., Conclusion: CP enlargement could be an independent risk factor for decreased cognition in patients with early-stage PD, and this risk may be mediated by CSF pathological proteins., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

The dichotomized brain system is a concept that was generalized from the 'dual syndrome hypothesis' to explain the heterogeneity of cognitive impairment, in which anterior and posterior brain systems are independent but partially overlap. The dopaminergic system acts on the anterior brain and is responsible for executive function, working memory, and planning. In contrast, the cholinergic system acts on the posterior brain and is responsible for semantic fluency and visuospatial function. Evidence from dopaminergic/cholinergic imaging or functional neuroimaging has shed significant insight relating to the involvement of the cerebellum in the cognitive process of patients with Parkinson's disease. Previous research has reported evidence that the cerebellum receives both dopaminergic and cholinergic projections. However, whether these two neurotransmitter systems are associated with cognitive function has yet to be fully elucidated. Furthermore, the precise role of the cerebellum in patients with Parkinson's disease and cognitive impairment remains unclear. Therefore, in this review, we summarize the cerebellar dopaminergic and cholinergic projections and their relationships with cognition, as reported by previous studies, and investigated the role of the cerebellum in patients with Parkinson's disease and cognitive impairment, as determined by functional neuroimaging. Our findings will help us to understand the role of the cerebellum in the mechanisms underlying cognitive impairment in Parkinson's disease., Competing Interests: None

Background: To investigate whether structural network disconnectivity is associated with parkinsonian signs and their progression, as well as with an increased risk of incident parkinsonism., Methods: In a prospective cohort (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort study) consisting of 293 participants with small vessel disease (SVD), we assessed parkinsonian signs and incident parkinsonism over an 8-year follow-up. In addition, we reconstructed the white matter network followed by graph-theoretical analyses to compute the network metrics. Conventional magnetic resonance imaging markers for SVD were assessed., Results: We included 293 patients free of parkinsonism at baseline (2011), with a mean age 68.8 (standard deviation [SD] 8.4) years, and 130 (44.4%) were men. Nineteen participants (6.5%) developed parkinsonism during a median (SD) follow-up time of 8.3 years. Compared with participants without parkinsonism, those with all-cause parkinsonism had higher Unified Parkinson's Disease Rating scale (UPDRS) scores and lower global efficiency at baseline. Baseline global efficiency was associated with UPDRS motor scores in 2011 (β = -0.047, p < .001) and 2015 (β = -0.84, p < .001), as well as with the changes in UPDRS scores during the 4-year follow-up (β = -0.63, p = .004). In addition, at the regional level, we identified an inter-hemispheric disconnected network associated with an increased UPDRS motor score. Besides, lower global efficiency was associated with an increased risk of all-cause and vascular parkinsonism independent of SVD markers., Conclusions: Our findings suggest that global network efficiency is associated with a gradual decline in motor performance, ultimately leading to incident parkinsonism in the elderly with SVD. Global network efficiency may have the added value to serve as a useful marker to capture changes in motor signs., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Objective: Our study aimed to explore the functional connectivity alterations between cortical nodes of resting-state networks in Parkinson's disease (PD) patients with wearing-off (WO) at different levels., Methods: Resting-state functional magnetic resonance imaging was performed on 36 PD patients without wearing-off (PD-nWO), 30 PD patients with wearing-off (PD-WO), and 35 healthy controls (HCs) to extract functional networks. Integrity, network, and edge levels were calculated for comparison between groups. UPDRS-III, MMSE, MOCA, HAMA, and HAMD scores were collected for further regression analysis., Results: We observed significantly reduced connectivity strength in the dorsal attention network and limbic network in the PD-WO group compared with the HC group. The PD-WO group showed a decreased degree of functional connectivity at 12 nodes, including the bilateral orbital part of the superior frontal gyrus, right olfactory cortex, left medial orbital part of the superior frontal gyrus, bilateral gyrus rectus, right parahippocampal gyrus, right thalamus, left Heschl's gyrus, right superior temporal gyrus part of the temporal pole, left middle temporal gyrus part of the temporal pole, and right inferior temporal gyrus. Furthermore, the PD-WO group showed a significantly lower degree of functional connectivity in the left orbital part of the superior frontal gyrus and right gyrus rectus than the PD-nWO group. Internetwork analysis indicated reduced functional connectivity in five pairs of resting-state networks., Conclusion: Our results demonstrated altered intra- and internetwork connections in PD patients with WO. These findings will facilitate a better understanding of the distinction between the network changes in PD pathophysiology., (© 2023. The Author(s).)

Our study aimed to investigate the grey matter (GM) changes using voxel-based morphometry (VBM) in Parkinson's disease (PD) patients with wearing-off (WO). 3D-T1-weighted imaging was performed on 48 PD patients without wearing-off (PD-nWO), 39 PD patients with wearing-off (PD-WO) and 47 age and sex-matched healthy controls (HCs). 3D structural images were analyzed by VBM procedure with Statistical Parametric Mapping (SPM12) to detect grey matter volume. Widespread areas of grey matter changes were found in patients among three groups (in bilateral frontal, temporal lobes, lingual gyrus, inferior occipital gyrus, right precuneus, right superior parietal gyrus and right cerebellum). Grey matter reductions were found in frontal lobe (right middle frontal gyrus, superior frontal gyrus and precentral gyrus), right parietal lobe (precuneus, superior parietal gyrus, postcentral gyrus), right temporal lobe (superior temporal gyrus, middle temporal gyrus), bilateral lingual gyrus and inferior occipital gyrus in PD-WO group compared with the PD-nWO group. Our results suggesting that wearing-off may be associated with grey matter atrophy in the cortical areas. These findings may aid in a better understanding of the brain degeneration process in PD with wearing-off., (© 2023. The Author(s).)

To explore the contribution of microorganisms to forest ecosystem function, we studied the ectomycorrhizal (ECM) fungal and soil bacterial community of the five typical tree species ( Pinus massoniana , PM; Castanopsis carlesii , CC; Castanopsis eyrei , CE; Castanopsis fargesii , CF; and Keteleeria cyclolepis , KC) at the Junzifeng National Nature Reserve. The results indicated that the ECM fungal and soil bacterial diversity of CC and CF was similar, and the diversity rates of CC and CF were higher than those of PM, CE, and KC. Cenococcum geophilum and unclassified&#95;Cortinariaceae II were the most prevalent occurring ECM fungi species in the five typical tree species, followed by unclassified&#95;Cortinariaceae I and Lactarius atrofuscus . In bacteria, the dominant bacterial genera were Acidothermus , Bradyrhizobium , Acidibacter , Candidatus&#95;Solibacter , Candidatus&#95;Koribacter , Roseiarcus , and Bryobacter . EMF fungi and soil bacteria were correlated with edaphic factors, especially the soil pH, TP, and TK, caused by stand development. The results show that the community characteristics of ECM fungi and bacteria in the typical tree species of the Junzifeng National Nature Reserve reflect the critical role of soil microorganisms in stabilizing forest ecosystems.

Objectives: This study explored the association between insomnia and the clinical outcome of large vessel occlusion Acute Ischemic Stroke (AIS) and attempted to explore its potential mechanisms from the perspectives of inflammation and oxidative stress., Methods: AIS patients who underwent endovascular treatment for large vessel occlusion at Binzhou Central Hospital from 2018 to 2022 (n = 508) were included. Patients were divided into an insomnia group and a non-insomnia group. Insomnia was judged by self-reported Athens Insomnia Scale score. Regression analysis was used to compare the differences in the 24-hour and 7-day National Institutes of Health Stroke Scale (NIHSS) score, Early Neurological Deterioration (END), early adverse event incidence, 90-day prognosis and mortality, and serum biomarkers levels., Results: The incidence of insomnia in the study population was 39.6% (n = 144, insomnia group; n = 364, non-insomnia group). Compared with the non-insomnia group, a worse prognosis outcome (63% vs. 49%, adjusted rate ratio: 1.8, 95% Confidence Interval: 1.2-3.7; p = 0.016), higher 24-h and 7-day NIHSS score (17 [9-36] vs. 13 [5-20]; p = 0.024, and 11 [4‒24) vs. 8 [2‒14]; p = 0.031, respectively), higher END (24% vs. 15%, p = 0.022), and higher incidence of adverse events were observed in the insomnia group (79% vs. 59%, p = 0.010). The 90-day mortality was higher in the insomnia group than that in the non-insomnia group (22% vs. 17%), however, such a difference was not statistically significant., Conclusion: Insomnia is closely related to the clinical outcome of AIS with large vessel occlusion, and inflammation and oxidative stress mechanisms may be involved., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2023 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

To investigate the molecular mechanism of communication network factor 1 (CCN1) regulating pentylenetetrazol (PTZ)-induced epileptogenesis, deepen the understanding of epilepsy seizure pathogenesis, and provide new drug action targets for its clinical prevention and treatment. Differentially expressed genes (DEGs) on microarrays GSE47516 and GSE88992 were analyzed online using GEO2R. Pathway enrichment and protein-protein interaction network (PPI) analysis of DEGs were carried out using Metascape. Brain tissue samples of severe traumatic brain injury patients (named Healthy group) and refractory epilepsy patients (named Epilepsy group) were obtained and analyzed by qRT-PCR and immunohistochemistry (IHC) staining. A PTZ-induced epilepsy mouse model was established and verified. Morphological changes of neurons in mouse brain tissue were detected using hematoxylin and eosin (HE) staining. qRT-PCR was conducted to detect the mRNA expressions of apoptosis-associated proteins Bax, Caspase-3 and bcl2. TUNEL staining was performed to detect brain neuron apoptosis. The levels of myocardial enzymology, GSH, MDA and ROS in blood of mouse were detected by biochemical assay. CCN1 expression was increased in epilepsy brain tissue samples. CCN1 decreasing effectively prolongs seizure incubation period and decreases seizure duration. Silencing of CCN1 also reduces neuronal damage and apoptosis, decreases mRNA and protein expression of proapoptotic proteins Bax and Caspase-3, increases mRNA expression of antiapoptotic protein Bcl2. Moreover, decrease of CCN1 decreases myocardial enzymatic indexes CK and CK-MB levels, reduces myocardial tissue hemorrhage, and relieves oxidative stress response in hippocampal and myocardial tissue. CCN1 expression is increased in epileptic samples. CCN1 decreasing protects brain tissue by attenuating oxidative stress and inhibiting neuronal apoptosis triggered by PTZ injection, which probably by regulating Nrf2/HO-1 pathway., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Chorea-acanthocytosis (ChAc) is a rare hereditary autosomal recessive neurodegenerative disorder caused by pathogenic variants of the Vacuolar Protein Sorting 13 homolog A (VPS13A) gene. The variant spectrum of VPS13A has not been completely elucidated. This study reports two novel heterozygous VPS13A pathogenic variants in ChAc that expand the variant spectrum of VPS13A., Case Presentation: We described a case of a 29-year-old man with typical clinical manifestations of ChAc, including chorea, orofacial lingual dyskinesia, vocal tics, elevated serum biochemical indicators, increased acanthocytes in peripheral blood, and caudate nucleus atrophy. Next-generation sequencing revealed two heterozygous variants of VPS13A: a nonsense variant (NM&#95;033305.2: c.8215G > T, p. Glu2739Ter) and a deletion variant in the exons 25-31., Conclusion: The identified nonsense variant gives rise to premature translation termination, while the deletion variant is expected to cause a significant in-frame deletion of amino acid residues in the encoded protein. Both variants are considered to be pathogenic and result in loss-of-function proteins. These findings have implications for the genetic counseling of patients with VPS13A variants., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: Emerging pathological evidence suggests that there is an association between glymphatic dysfunction and the progression of Parkinson's disease (PD). However, the clinical evidence of this association remains lacking., Methods: In this study, the index for diffusion tensor image analysis along the perivascular space (ALPS index) was calculated to evaluate glymphatic function., Results: Overall, 289 patients with PD were enrolled in the cross-sectional study. The ALPS index was found to be negatively correlated with age, disease severity, and dyskinesia. In the longitudinal study, the information on a total of 95 PD patients with 5-year follow-up examinations was collected from the Parkinson's Progression Marker Initiative, 33 of which were classified into the low ALPS index group, and all others were classified into the mid-high ALPS index group based on the first tertile of the baseline ALPS index. The results of longitudinal regression indicated that there was a significant main group effect on autonomic dysfunction, as well as on activities of daily living. In addition, the low ALPS index group had faster deterioration in MDS-UPDRS part III and part II, Symbol Digit Modalities Test and Hopkins Verbal Learning Test. Path analysis showed that ALPS index acted as a significant mediator between tTau/ Aβ 1-42 and cognitive change in the Symbol Digit Modalities Test score at year 4 and year 5., Interpretation: The ALPS index, an neuroimaging marker of glymphatic function, is correlated with PD disease severity, motor symptoms, and autonomic function, and is predictive of faster deterioration in motor symptoms and cognitive function. Additionally, glymphatic function may mediate the pathological role of toxic protein in cognitive decline. ANN NEUROL 2023;94:672-683., (© 2023 American Neurological Association.)

Background: Substantial heterogeneity of motor symptoms in Parkinson's disease (PD) poses a challenge to disease prediction., Objectives: The aim of this study was to construct a nomogram model that can distinguish different longitudinal trajectories of motor symptom changes in early-stage PD patients., Methods: Data on 90 patients with 5-years of follow-up were collected from the Parkinson's Progression Marker Initiative (PPMI) cohort. We used a latent class mixed modeling (LCMM) to identify distinct progression patterns of motor symptoms, and backward stepwise logistic regression with baseline information was conducted to identify the potential predictors for motor trajectory and to develop a nomogram. The performance of the nomogram model was then evaluated using the optimism-corrected C-index for internal validation, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve for discrimination, the calibration curve for predictive accuracy, and decision curve analysis (DCA) for its clinical value., Results: We identified two trajectories for motor progression patterns. The first, Class 1 (Motor deteriorated group), was characterized by sustained, continuously worsening motor symptoms, and the second, Class 2 (Motor stable group), had stable motor symptoms throughout the follow-up period. The best combination of 7 baseline variables was identified and assembled into the nomogram: Scopa-AUT [odds ratio (OR), 1.11; p = 0.091], Letter number sequencing (LNS) (OR, 0.76; p = 0.068), the asymmetry index of putamen (OR, 0.95; p = 0.034), mean caudate uptake (OR, 0.14; p = 0.086), CSF pTau/α-synuclein (OR, 0.00; p = 0.011), CSF tTau/Aβ (OR, 25434806; p = 0.025), and the index for diffusion tensor image analysis along the perivascular space (ALPS-index) (OR, 0.02; p = 0.030). The nomogram achieved good discrimination, with an original AUC of 0.901 (95% CI, 0.813-0.989), and the bias-corrected concordance index (C-index) with 1,000 bootstraps was 0.834. The calibration curve and DCA also suggested both the high accuracy and clinical usefulness of the nomogram, respectively., Conclusions: This study proposes an effective nomogram to predict different motor progression patterns in early-stage PD. Furthermore, the imaging biomarker indicating glymphatic function could be an independent predictive factor for PD motor progression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Pinus massoniana (Massion's pine) , a pioneer tree species, exhibits restoration potential in polluted mining areas. However, the physiological and molecular mechanisms of ectomycorrhizal (ECM) fungi in Massion's pine adaptability to multiple-toxic-metal stress are still unclear. Hence, Massion's pine seedlings inoculated with two strains of C. geophilum , which were screened and isolated from a polluted mine area, were cultivated in mine soil for 90 days to investigate the roles of EMF in mediating toxic metal tolerance in host plants. The results showed that compared with the non-inoculation control, C. geophilum (CG1 and CG2) significantly promoted the biomass, root morphology, element absorption, photosynthetic characteristics, antioxidant enzyme activities (CAT, POD, and SOD), and proline content of Massion's pine seedlings in mine soil. C. geophilum increased the concentrations of Cr, Cd, Pb, and Mn in the roots of Massion's pine seedlings, with CG1 significantly increasing the concentrations of Pb and Mn by 246% and 162% and CG2 significantly increasing the concentrations of Cr and Pb by 102% and 78%. In contrast, C. geophilum reduced the concentrations of Cr, Cd, Pb, and Mn in the shoots by 14%, 33%, 27%, and 14% on average, respectively. In addition, C. geophilum significantly reduced the transfer factor (TF) of Cr, Cd, Pb, and Mn by 32-58%, 17-26%, 68-75%, and 18-64%, respectively, and the bio-concentration factor (BF) of Cd by 39-71%. Comparative transcriptomic analysis demonstrated that the differently expressed genes (DEGs) were mainly encoding functions involved in "transmembrane transport", "ion transport", "oxidation reduction process", "oxidative phosphorylation", "carbon metabolism", "glycolysis/gluconeogenesis", "photosynthesis", and "biosynthesis of amino acids." These results indicate that C. geophilum is able to mitigate toxic metals stress by promoting nutrient uptake, photosynthesis, and plant growth, thereby modulating the antioxidant system to reduce oxidative stress and reducing the transport and enrichment of toxic metals from the root to the shoot of Massion's pine seedlings.

The pathological accumulation of α-synuclein (α-Syn) and the transmission of misfolded α-Syn underlie α-synucleinopathies. Increased plasma α-Syn levels are associated with cognitive impairment in Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies, but it is still unknown whether the cognitive deficits in α-synucleinopathies have a common vascular pathological origin. Here, it is reported that combined injection of α-Syn preformed fibrils (PFFs) in the unilateral substantia nigra pars compacta, hippocampus, and cerebral cortex results in impaired spatial learning and memory abilities at 6 months post-injection and that this cognitive decline is related to cerebral microvascular injury. Moreover, insoluble α-Syn inclusions are found to form in primary mouse brain microvascular endothelial cells (BMVECs) through lymphocyte-activation gene 3 (Lag3)-dependent α-Syn PFFs endocytosis, causing poly(ADP-ribose)-driven cell death and reducing the expression of tight junction proteins in BMVECs. Knockout of Lag3 in vitro prevents α-Syn PFFs from entering BMVECs, thereby reducing the abovementioned response induced by α-Syn PFFs. Deletion of endothelial cell-specific Lag3 in vivo reverses the negative effects of α-Syn PFFs on cerebral microvessels and cognitive function. In short, this study reveals the effectiveness of targeting Lag3 to block the spread of α-Syn fibrils to endothelial cells in order to improve cognition., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

α-Synuclein preformed fibrils (α-syn PFF) in the blood can cross the blood-brain barrier and invade the central nervous system. Our previous study proved that α-syn PFF can be taken up by brain microvascular endothelial cells (BMVECs). Here, we found that α-syn PFF spread from BMVECs to pericytes with the highest transmission efficiency. We observed abundant tunneling nanotubes (TNTs) connecting BMVECs and pericytes, and α-syn PFF transmitted through these TNTs. Furthermore, α-syn PFF accumulation in BMVECs did not promote TNT formation, but activated the molecular motor Myo1d. Inhibition of Myo1d prevented α-syn PFF transfer from BMVECs to pericytes and decreased the colocalization of Myo1d and F-actin in BMVECs. In summary, we are the first to demonstrate that α-syn PFF spread from BMVECs to pericytes through a mechanism involving TNTs and myosin. Targeting Myo1d may be a promising approach to prevent α-syn spreading from the blood to the brain., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Background: Repetitive transcranial magnetic stimulation (rTMS) is a potential treatment option for Parkinson's disease patients with depression (DPD), but conflicting results in previous studies have questioned its efficacy., Method: To investigate the safety and efficacy of neuronavigated high-frequency rTMS at the left DLPFC in DPD patients, we conducted a randomized, double-blind, sham-controlled study (NCT04707378). Sixty patients were randomly assigned to either a sham or active stimulation group and received rTMS for ten consecutive days. The primary outcome was HAMD, while secondary outcomes included HAMA, MMSE, MoCA and MDS-UPDRS-III. Assessments were performed at baseline, immediately after treatment, 2 weeks, and 4 weeks post-treatment., Results: The GEE analysis showed that the active stimulation group had significant improvements in depression, anxiety, and motor symptoms at various time points. Specifically, there were significant time-by-group interaction effects in depression immediately after treatment (β, -4.34 [95% CI, -6.90 to -1.74; P  = 0.001]), at 2 weeks post-treatment (β, -3.66 [95% CI, -6.43 to -0.90; P  = 0.010]), and at 4 weeks post-treatment (β, -4.94 [95% CI, -7.60 to -2.29; P  < 0.001]). Similarly, there were significant time-by-group interaction effects in anxiety at 4 weeks post-treatment (β, -2.65 [95% CI, -4.96 to -0.34; P  = 0.024]) and in motor symptoms immediately after treatment (β, -5.72 [95% CI, -9.10 to -2.34; P  = 0.001] and at 4 weeks post-treatment (β, -5.43 [95% CI, -10.24 to -0.61; P  = 0.027])., Conclusion: The study suggested that neuronavigated high-frequency rTMS at left DLPFC is effective for depression, anxiety, and motor symptoms in PD patients., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (© 2023 The Authors.)

Neurovascular imaging is essential for investigating neurodegenerative diseases. However, the existing neurovascular imaging technology suffers from a trade-off between a field of view (FOV) and resolution in the whole brain, resulting in an inhomogeneous resolution and lack of information. Here, homogeneous-resolution arched-scanning photoacoustic microscopy (AS-PAM), which has an ultrawide FOV to cover the entire mouse cerebral cortex, was developed. Imaging of the neurovasculature was performed with a homogenous resolution of 6.9 µm from the superior sagittal sinus to the middle cerebral artery and caudal rhinal vein in an FOV of 12 × 12 mm 2 . Moreover, using AS-PAM, vascular features of the meninges and cortex were quantified in early Alzheimer's disease (AD) and wild-type (WT) mice. The results demonstrated high sensitivity to the pathological progression of AD on tortuosity and branch index. The high-fidelity imaging capability in large FOV enables AS-PAM to be a promising tool for precise brain neurovascular visualization and quantification., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Cholinergic basal forebrain (BF) pathology is a hallmark of Parkinson's disease (PD) with mild cognitive impairment (PD-MCI). Assessment of functional connectivity (FC) of different cholinergic BF nuclei may deepen the understanding of PD-MCI pathogenesis., Methods: Seed-based FC analysis was performed with bilateral medial septal nucleus, the nucleus of the vertical limb of the diagonal band, nucleus of the horizontal limb of the diagonal band (Ch1-3), and the nucleus basalis of Meynert (NBM/Ch4) to explore the BF functional alterations in different frequency bands. Correlations between FC values of abnormal regions and scores of cognitive domains and depression in the PD group were also assessed., Results: For the right Ch4, in the conventional frequency band, the PD-MCI group exhibited lower FC values in the right middle cingulate and paracingulate gyri, middle frontal gyrus, left inferior parietal gyrus, and superior frontal gyrus compared with healthy controls (HC), and in the left calcarine fissure and surrounding cortex compared with PD with normal cognition (PD-NC). For the slow 4 subbands, the PD-MCI group showed significantly lower FC values in the left putamen, middle frontal gyrus, right middle frontal gyrus, and precuneus compared with HC, and in right middle frontal gyrus cingulate and paracingulate gyri compared with the PD-NC group. For the slow 5 subbands, the PD-MCI group showed increased FC values in the right calcarine fissure and surrounding cortex, and left cerebellum. For the left Ch1-3, FC values in the right middle cingulate and paracingulate gyri were lower in patients with PD-MCI than in the PD-NC group in slow 4 subbands. Furthermore, altered FC values in the cortical regions for Ch4 seed were possibly correlated with depression and different cognitive domain scores., Conclusions: The study identified an imbalanced association between different cholinergic BF nuclei and cortical regions in patients with PD-MCI, and showed that FC changes are frequency-specific, which may provide new insights into functional alterations within the cholinergic system in cognitive impairment associated with PD., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-22-582/coif). The authors have no conflicts of interest to declare., (2023 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Cerebellar dysfunction may substantially contribute to the clinical symptoms of Parkinson's disease (PD). The role of cerebellar subregions in tremors and gait disturbances in PD remains unknown. To investigate alterations in cerebellar subregion volumes and functional connectivity (FC), as well as FC between the dentate nucleus (DN) and ventral lateral posterior nucleus (VLp) of the thalamus, which are potentially involved in different PD motor subtypes. We conducted morphometric and resting-state functional connectivity analyses in various cerebellar subregions in 22 tremor-dominant (TD)-PD and 35 postural instability gait difficulty dominant (PIGD)-PD patients and 38 sex- and age-matched healthy controls (HCs). The volume and FC alterations in various cerebellar subregions and the neural correlates of these changes with the clinical severity scores were investigated. The PIGD-PD group showed greater FC between the right motor cerebellum (CBMm) and left postcentral gyrus than the HC group, and a higher FC was associated with less severe PIGD symptoms. In contrast, the TD-PD group had decreased FC between the right DN and left VLp compared with the PIGD-PD and HC groups, and lower FC was associated with worse TD symptoms. Furthermore, the PIGD-PD group had higher FC between the left DN and left inferior temporal gyrus than the TD-PD group. Morphometric analysis revealed that the TD-PD group showed a significantly higher volume of left CBMm than the HC group. Our findings point to differential alteration patterns in cerebellar subregions and offer a new perspective on the pathophysiology of motor subtypes of PD., (© 2023. The Author(s).)

One of the important pathological features of Parkinson's disease (PD) is the pathological aggregation of α-synuclein (α-Syn) in the substantia nigra. Preventing the aggregation of α-Syn has become a potential strategy for treating PD. However, the molecular mechanism of α-Syn aggregation is unclear. In this study, using the dynamic network biomarker (DNB) method, we first identified the critical time point when α-Syn undergoes pathological aggregation based on a SH-SY5Y cell model and found that DNB genes encode transcription factors that regulated target genes that were differentially expressed. Interestingly, we found that these DNB genes and their neighbouring genes were significantly enriched in the cellular senescence pathway and thus proposed that the DNB genes HSF1 and MAPKAPK2 regulate the expression of the neighbouring gene SERPINE1. Notably, in Gene Expression Omnibus (GEO) data obtained from substantia nigra, prefrontal cortex and peripheral blood samples, the expression level of MAPKAPK2 was significantly higher in PD patients than in healthy people, suggesting that MAPKAPK2 has potential as an early diagnostic biomarker of diseases related to pathological aggregation of α-Syn, such as PD. These findings provide new insights into the mechanisms underlying the pathological aggregation of α-Syn., (© 2023. The Author(s).)

Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons and accumulation of misfolded alpha-synuclein (αSyn) into Lewy bodies. In addition to motor impairment, PD commonly presents with cognitive impairment, a non-motor symptom with poor outcome. Cortical αSyn pathology correlates closely with vascular risk factors and vascular degeneration in cognitive impairment. However, how the brain microvasculature regulates αSyn pathology and neurodegeneration remains unclear. Here, we constructed a rapidly progressive PD model by injecting alpha-synuclein preformed fibrils (αSyn PFFs) into the cerebral cortex and striatum. Brain capillaries in mice with cognitive impairment showed a reduction in diameter and length after 6 months, along with string vessel formation. The intracellular domain of low-density lipoprotein receptor-related protein-1 (LRP1-ICD) was upregulated in brain microvascular endothelium. LRP1-ICD promoted αSyn PFF uptake and exacerbated endothelial damage and neuronal apoptosis. Then, we overexpressed LRP1-ICD in brain capillaries using an adeno-associated virus carrying an endothelial-specific promoter. Endothelial LRP1-ICD worsened αSyn PFF-induced vascular damage, αSyn pathology, or neuron death in the cortex and hippocampus, resulting in severe motor and cognitive impairment. LRP1-ICD increased the synthesis of poly(adenosine 5'-diphosphate-ribose) (PAR) in the presence of αSyn PFFs. Inhibition of PAR polymerase 1 (PARP1) prevented vascular-derived injury, as did loss of PARP1 in the endothelium, which was further implicated in endothelial cell proliferation and inflammation. Together, we demonstrate a novel vascular mechanism of cognitive impairment in PD. These findings support a role for endothelial LRP1-ICD/PARP1 in αSyn pathology and neurodegeneration, and provide evidence for vascular protection strategies in PD therapy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: The aim of the study was to evaluate the glymphatic function and its related factors in patients with Parkinson's disease (PD) and patients with PD of different ages using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method., Methods: Medical records and imaging data of 93 patients with idiopathic PD and 42 age- and sex-matched healthy controls (HCs) were retrospectively reviewed and analyzed. The diffusivity along the perivascular spaces, projection fibers, and association fibers were calculated on diffusion tensor imaging (DTI) to acquire the analysis along the perivascular space (ALPS) index., Results: PD patients exhibited a reduced ALPS index compared with the HCs. Negative correlations between the ALPS index and clinical information including age, age at disease onset, Parkinson's disease sleep scale 2nd version (PDSS-2) scores, and history of diabetes mellitus were revealed in the PD group. Besides, a negative correlation between the ALPS index and the severity of motor symptoms was identified in the subgroup aged 65 and above, rather than in the younger ones., Conclusions: The results demonstrate that reduced ALPS index, a potential noninvasive measure of compromised glymphatic activity, is involved in the pathophysiology of PD, especially in the aged ones and those with sleep disorders., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Objective: To explore the potential clinical effects of renin-angiotensin system blocker (RASB, angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs)) in patients from the Parkinson's Progress Marker Initiative (PPMI) study database., Methods: One hundred and seven untreated, newly diagnosed PD patients with hypertension, from the PPMI were included. We measured cognitive performance, biomarkers in CSF, and magnetic resonance imaging (MRI) during the five follow-up years for patients exposed or not to renal-angiotensin system blockers. Sixteen PD patients with hypertension underwent [18F]florbetaben positron emission tomography (PET) scanning. SUVRs of region of interest (ROI) were calculated and compared within different groups., Result: Treatment with ARBs but not ACEIs improved global cognitive function evaluated by MoCA score in PD patients with hypertension compared to other hypertensive medicines up to 5 years follow up. Specifically, ARBs improved visuospatial, memory, executive abilities, processing speed attention test scores in PD. There was no significant impact of ARBs on α-syn, tau, Aβ in CSF. RASBs reduced [18F] florbetaben uptake in cortex and subcortex nuclei in the brain., Conclusions: These results show potential protective effect with ARBs in cognitive impairment of parkinson's disease with hypertension., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Proposed mechanisms for the production of calcium in the first stars (population III stars)-primordial stars that formed out of the matter of the Big Bang-are at odds with observations 1 . Advanced nuclear burning and supernovae were thought to be the dominant source of the calcium production seen in all stars 2 . Here we suggest a qualitatively different path to calcium production through breakout from the 'warm' carbon-nitrogen-oxygen (CNO) cycle through a direct experimental measurement of the 19 F(p, γ) 20 Ne breakout reaction down to a very low energy point of 186 kiloelectronvolts, reporting a key resonance at 225 kiloelectronvolts. In the domain of astrophysical interest 2 , at around 0.1 gigakelvin, this thermonuclear 19 F(p, γ) 20 Ne rate is up to a factor of 7.4 larger than the previous recommended rate 3 . Our stellar models show a stronger breakout during stellar hydrogen burning than previously thought 1,4,5 , and may reveal the nature of calcium production in population III stars imprinted on the oldest known ultra-iron-poor star, SMSS0313-6708 6 . Our experimental result was obtained in the China JinPing Underground Laboratory 7 , which offers an environment with an extremely low cosmic-ray-induced background 8 . Our rate showcases the effect that faint population III star supernovae can have on the nucleosynthesis observed in the oldest known stars and first galaxies, which are key mission targets of the James Webb Space Telescope 9 ., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Energy-saving reconstruction of old residential buildings is a vital way to achieve sustainable development, but the potential of rooftop photovoltaic (PV) energy-saving in old residential buildings has not been studied. This study established a basic framework for the estimation of rooftop PV technical, economic and environmental potential in the old residential buildings of Nanjing City, and provide the prediction results for the development of rooftop PV development plan in Nanjing. We estimated the available area, maximum electricity generation, environmental and economic benefits of rooftop PV in five districts of Nanjing by using building roof profile data, calculation method of maximum solar radiation at optimal tilt angle and GIS method. We find that the electricity generation potential of installing rooftop PV in the old residential buildings in the study area would meet about 17.7-20% of the residential electricity demand under three scenarios of the PV performance ratios (PR). Additionally, the carbon reduction potential of the life cycle rooftop PV reaches 13912874.12t (PR = 0.85), 13094469.76t (PR = 0.8), and 12276065.4t (PR = 0.75), respectively; and the result of economic potential shows that the life cycle of rooftop PV cannot generate economic benefits with an NPV value less than 0. The feasibility analysis framework provided in this paper can be applied to the assessment of rooftop PV potential in other cities in China, and provide valuable advice for the rational planning of rooftop PV., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: We employed quantitative susceptibility mapping (QSM) to assess iron deposition in parkinsonian disorders and explored whether combining QSM values and neurofilament light (NfL) chain levels can improve the accuracy of distinguishing Parkinson's disease (PD) from multiple system atrophy (MSA) and progressive supranuclear palsy (PSP)., Materials and Methods: Forty-seven patients with PD, 28 patients with MSA, 18 patients with PSP, and 28 healthy controls (HC) were enrolled, and QSM data were reconstructed. Susceptibility values in the bilateral globus pallidus (GP), putamen (PUT), caudate nucleus (CN), red nucleus (RN), substantia nigra (SN), and dentate nucleus (DN) were obtained. Plasma NfL levels of 47 PD, 18 MSA, and 14 PSP patients and 22 HC were measured by ultrasensitive Simoa technology., Results: The highest diagnostic accuracy distinguishing MSA from PD patients was observed with increased susceptibility values in CN (AUC: 0.740). The susceptibility values in RN yielded the highest diagnostic performance for distinguishing PSP from PD patients (AUC: 0.829). Plasma NfL levels were significantly higher in the MSA and PSP groups than in PD and HC groups. Combining the susceptibility values in the RN and plasma NfL levels improved the diagnostic performance for PSP vs. PD (AUC: 0.904), whereas plasma NfL levels had higher diagnostic accuracy for MSA vs. PD (AUC: 0.877)., Conclusion: The exploratory study indicates different patterns of iron accumulation in deep gray matter nuclei in Parkinsonian disorders. Combining QSM values with NfL levels may be a promising biomarker for distinguishing PSP from PD, whereas plasma NfL may be a reliable biomarker for differentiating MSA from PD. QSM and NfL measures appeared to have low accuracy for separating PD from controls., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Chen, Cai, He, Li, Li, Chen, Wang and Zhang.)

Background: Processing speed and executive function can be impaired in patients with Parkinson disease (PD). However, the neural factors related to the slowdown in processing speed and dysexecutive function in PD are not completely understood. The objective of this study is to investigate the metabolic changes of the frontal and anterior cingulate cortex (ACC) through the use of 1 H magnetic resonance spectroscopy and to explore the association between cognitive function and metabolic ratios., Methods: In this retrospective case-control study, we conducted neuropsychological assessments of executive function and information processing speed in healthy controls (HCs) and in patients with PD. Chemical information was obtained for the of N-acetyl-aspartate (NAA):creatine (Cr) ratio and the choline-containing compounds (Cho):Cr ratio within the bilateral prefrontal cortex and ACC. Using hierarchical multiple regression analysis, we analyzed the relationship between cognitive function and metabolic ratios in the bilateral prefrontal lobe and ACC in patients with PD., Results: In all, 59 patients with PD and 30 HCs were recruited. Patients with PD showed worse performance in executive function and processing speed compared with HCs (P<0.001). In patients with PD, the Cho:Cr ratios in the ACC (Z=2.20, P=0.028) and the right prefrontal cortex ( t =2.16, P=0.034) were significantly increased. The hierarchical multiple regressions in patients with PD showed that the NAA:Cr ratio in the ACC correlated with the Stroop A completion times (P<0.05) and that the NAA:Cr ratio of the right prefrontal cortex correlated with the scores of the Wechsler Adult Intelligence Scale (WAIS)-Digit symbol test (P<0.05)., Conclusions: Information processing speed and executive function are impaired in patients with PD. Neuronal integrity and membrane turnover in the ACC and the right prefrontal cortex may be important factors in the slowdown of the information processing speed in patients with PD., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-21-1126/coif). The authors have no conflicts of interest to declare., (2022 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Backgrounds: Bile acid (BA) plays a crucial role in various neurodegenerative diseases, including Parkinson's disease (PD). However, no clinical evidence supports BA's potential role in patients with PD with mild cognitive impairment (PD-MCI)., Objectives: This study aimed at investigating the differential BA profile between patients with PD-MCI and those with normal cognitive function (PD-NC)., Methods: Ultra-high performance liquid chromatography-MS/MS was applied for BA quantitation. After between-group differences of the BA profile were addressed, orthogonal projections to latent structures-discriminant analysis (OPLS-DA) and the area under the receiver-operating-characteristic curve (AUC-ROC) were implemented for further verification., Results: Lower levels of chenodeoxycholic acid (CDCA), cholic acid (CA), and ursodeoxycholic acid (UDCA) were significantly associated with PD-MCI ( p < 0.01 for both; VIP ≈ 2.67, 1.66, and 1.26, respectively). AUC-ROC were 78.1, 74.2, and 74.5% for CDCA, CA, and UDCA, respectively., Conclusion: CA, CDCA, and UDCA might be distinct BA signatures for patients with PD-MCI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nie, Li, Zhang, Gao, Qiu, Gan, Zhang and Wang.)

Objective: To investigate white matter microstructural alterations in Parkinson's disease (PD) patients with depression using the whole-brain diffusion tensor imaging (DTI) method and to explore the DTI-based machine learning model in identifying depressed PD (dPD)., Methods: The DTI data were collected from 37 patients with dPD and 35 patients with non-depressed PD (ndPD), and 25 healthy control (HC) subjects were collected as the reference. An atlas-based analysis method was used to compare fractional anisotropy (FA) and mean diffusivity (MD) among the three groups. A support vector machine (SVM) was trained to examine the probability of discriminating between dPD and ndPD., Results: As compared with ndPD, dPD group exhibited significantly decreased FA in the bilateral corticospinal tract, right cingulum (cingulate gyrus), left cingulum hippocampus, bilateral inferior longitudinal fasciculus, and bilateral superior longitudinal fasciculus, and increased MD in the right cingulum (cingulate gyrus) and left superior longitudinal fasciculus-temporal part. For discriminating between dPD and ndPD, the SVM model with DTI features exhibited an accuracy of 0.70 in the training set [area under the receiver operating characteristic curve (ROC) was 0.78] and an accuracy of 0.73 in the test set (area under the ROC was 0.71)., Conclusion: Depression in PD is associated with white matter microstructural alterations. The SVM machine learning model based on DTI parameters could be valuable for the individualized diagnosis of dPD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Yang, Pan, Xu, Wang, Zhang, Nie and Huang.)

Parkinson's disease (PD) is one of the most common chronic progressive neurodegenerative diseases that affects both motor and non-motor functions. Bile acids modulate the immune system by targeting brain receptors. INT-777, a 6α-ethyl-23(S)-methyl derivative of cholic acid (S-EMCA), acts as an agonist for Takeda G protein-coupled receptor-5 (TGR5) and has neuroprotective properties. However, the effects of INT-777 on PD have not yet been investigated. In a subchronic PD model, mice treated with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) developed motor deficits and cognitive impairment that were ameliorated after intranasal administration of INT-777. INT-777 prevented MPTP-induced neurodegeneration and microglia activation in the substantia nigra pars compacta, hippocampus, and cortical layer V. Based on bioinformatics and wet lab data, INT-777 inhibited microglia activation by suppressing the release of tumor necrosis factor alpha (TNF-α) in the hippocampus, along with secondary chemokines (C-C motif ligand 3 (CCL3) and CCL6) in these three brain regions. INT-777 inhibited TNF-α production by repairing mitochondrial damage, which was associated with nuclear factor-erythroid 2-related factor-2 (NRF2) activation and p62/LC3B-mediated autophagy. INT-777 reversed the downregulation of heme oxygenase-1 (HO1), NAD(P)H quinone oxidoreductase-1 (NQO1) and accumulation of p62 in microglia treated with 1-methyl-4-phenylpyridinium (MPP+). However, TGR5 knockdown in microglia abolished INT-777's inhibition of TNF-α release, resulting in neuronal death. Therefore, PD cognitive impairment is associated with hippocampal TNF-α elevation as a result of mitochondrial damage in microglia. Our data reveal the potential role of TGR5 in modulating inflammation-mediated neurodegeneration in PD, and provides new insights for bile acid metabolites as promising disease-modifying drugs for PD., Competing Interests: Declaration of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Parkinson's disease (PD) is associated with structural alterations of the retina. However, it remains unknown whether these changes are present in PD with mild cognitive impairment (MCI). The purpose of the study was to evaluate the retinal microvasculature using optical coherence tomography angiography (OCTA) to assess possible retinal microvascular impairments associated with PD and PD with MCI., Methods: This study included 83 eyes of 45 PD patients and 83 eyes of 42 healthy controls. All subjects underwent complete neurological and ophthalmological examinations before measurements. Cognitive function was also measured in PD patients. Retinal microvasculature was evaluated with OCTA. Vessel density in the superficial capillary plexus (SRCP), deep capillary plexus (DRCP), and radial peripapillary capillaries (RPC) and intraretinal layer thickness in the peripapillary retinal nerve fibre layer (RNFL) and ganglion cell complex (GCC) were analysed. Correlations between vessel density and cognitive function were analysed in the PD group., Results: Parafoveal vessel density in the SRCP and DRCP were lower in the eyes of PD patients than healthy controls (P < 0.05). However, there were no significant differences in the RPC (P = 0.120), RNFL (P = 0.303) or GCC (P = 0.375) between PD patients and healthy controls. Lower executive function scores were associated with lower vessel density in the DRCP of PD patients (P < 0.05, 95% CI [0.133,1.342])., Conclusion: OCTA revealed lower macular microvascular density in PD patients and microvascular impairments in the deep retinal capillary layer in PD patients with executive dysfunction. These parameters might have potential utility as early disease diagnostic biomarkers., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To analyse the changes of quantitative electroencephalogram (qEEG) and cortex structural magnetic resonance (MR) imaging in Parkinson's disease with mild cognitive impairment (PD-MCI) and to explore the "composite marker"-based machine learning model in identifying PD-MCI., Methods: Retrospective analysis of patients with PD identified 36 PD-MCI and 35 PD with normal cognition (PD-NC). QEEG features of power spectrum and structural MR features of cortex based on surface-based morphometry (SBM) were extracted. Support vector machine (SVM) was established using combined features of structural MR and qEEG to identify PD-MCI. Feature importance evaluation algorithm of mean impact value (MIV) was established to sort the vital characteristics of qEEG and structural MR., Results: Compared with PD-NC, PD-MCI showed a statistically significant difference in 5 leads and waves of qEEG and 7 cortical region features of structural MR. The SVM model based on these qEEG and structural MR features yielded an accuracy of 0.80 in the training set and had a high prediction accuracy of 0.80 in the test set (sensitivity was 0.78, specificity was 0.83, area under the receiver operating characteristic curve was 0.77), which was higher than the model built by the feature separately. QEEG features of theta wave in C3 had a marked impact on the model for classification according to the MIV algorithm., Conclusions: PD-MCI is characterized by widespread structural and EEG abnormality. "Composite markers" could be valuable for the individualized diagnosis of PD-MCI by machine learning., Key Points: • Explore the brain abnormalities in Parkinson's disease with mild cognitive impairment by using the quantitative electroencephalogram and cortex structural MR simultaneously. • Multimodal features based support vector machine for identifying Parkinson's disease with mild cognitive impairment has an acceptable performance. • Theta wave in C3 is the most influential feature of qEEG and cortex structure MR imaging in identifying Parkinson's disease with mild cognitive impairment using support vector machine., (© 2021. European Society of Radiology.)

Background : Abnormal spontaneous neural activity is often found in patients with Parkinson's disease with mild cognitive impairment (PD-MCI). However, the frequency dependence of neuronal interaction activities, especially the fractional amplitude of low-frequency fluctuation (fALFF) and degree centrality (DC), in PD-MCI is still unclear. Thus, this study aimed to explore the frequency dependence of PD-MCI based on fALFF and DC maps. Methods : Twenty-four patients with PD-MCI, 42 PD patients with normal cognition (PD-NC), and 33 healthy controls (HCs) were enrolled. Neuropsychological assessments and resting-state functional MRI (rs-fMRI) were performed. The fALFF and DC values in the conventional, slow4 and slow5 frequency bands were compared among the groups. Results : In the conventional frequency band, the DC value in the left precentral area was decreased in PD-MCI patients, while that in the right fusiform area was increased in PD-NC patients compared with HCs. Regarding fALFFs, both the PD-MCI and PD-NC patients had decreased values in the right precentral area compared with those of the HCs. The fALFFs did not differ between PD-MCI and PD-NC patients. The fALFF results in the slow4 subfrequency band were consistent with those in the conventional frequency band. In the slow5 band, the DC value in the left middle temporal lobe was higher in PD-MCI patients than in PD-NC patients and was positively correlated with the performance of the PD-MCI patients on the Montreal Cognitive Assessment (MoCA). Additionally, both PD-MCI and PD-NC patients showed lower fALFF values in the bilateral putamen than the HCs, and the fALFF in the bilateral putamen was negatively correlated with the Hoehn and Yahr stages of PD-MCI. The fALFF in the left putamen was negatively correlated with the scores of PD-MCI patients on the Movement Disorder Society-Unified Parkinson Disease Rating Scale Part III (MDS-UPRDS-III). Conclusion : Our results suggested that abnormal neuronal activities, such as fALFF and DC, are dependent on frequency in PD-MCI. Some subfrequency bands could distinguish PD-MCI from PD. Our findings may be helpful for further revealing the frequency-dependent resting functional disruption in PD-MCI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rong, Zhang, He, Li, Li, Li, Nie, Huang, Wang, Wang and Zhang.)

Parkinson's disease (PD) is the second most neurodegenerative disease in the world. T cell infiltration in the central nervous system (CNS) has provided insights that the peripheral immune cells participate in the pathogenesis of PD. However, the association between the peripheral immune system and CNS remains to be elucidated. In this study, we analyzed incorporative substantia nigra (SN) expression data and blood expression data using the CIBERSORT to obtain the 22 immune cell fractions and then explored the molecular function to identify the potential key immune cell types and genes of PD. We observed that the proportions of naïve CD4 T cells, gamma delta T cells, resting natural killer (NK) cells, neutrophils in the blood, and regulatory T cells (Tregs) in the SN were significantly different between patients with PD and healthy controls (HCs). We identified p53-induced death domain protein 1 ( PIDD1 ) as the hub gene of a PD-related module. The enrichment score of the neuron-specific gene set was significantly different between PD and HC, and genes in the neuron-related module were enriched in the biological process about mitochondria and synapses. These results suggested that the fractions of naïve CD4 T cells, gamma delta T cells, resting NK cells, and neutrophils may be used as a combined diagnostic marker in the blood, and Tregs in SN may be a potential therapeutic design target for PD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Huang, Liu, Hu, Han, Zhong, Luo, Zhang and Ling.)

This study aimed to investigate the influence of serum folate, vitamin B12 (VitB12) levels, and inflammation-based scores on the motor performance status in Parkinson's disease (PD). We retrospectively collected data from 148 consecutive patients with idiopathic PD first admitted to our hospital. We measured whole blood count, albumin, lactate dehydrogenase, C-reactive protein, folate, and VitB12 levels and calculated the inflammation-based scores. The following scales were applied to assess the motor performance status: activity of daily living scale (ADL, the Barthel Index), the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III), and Hoehn-Yahr (H-Y) classification. The geometric mean of folate and VitB12 levels were 11.87 (ng/ml) and 330.52 (pmol/L), respectively. Folate deficiency (serum level < 4.0 ng/ml) and VitB12 deficiency (serum level < 133 pg/ml) were present in 0.7 and 5.4% of the patients, respectively. The mean prognostic nutritional index (PNI) and systemic immune-inflammation index (SII) were 47.78 ± 4.42 and 470.81 ± 254.05, respectively. The multivariate analyses showed that serum VitB12 level ( P = 0.002) and SII ( P = 0.005) were significant factors for ADL score; serum folate ( P = 0.027) and VitB12 ( P = 0.037) levels for UPDRS-III score; and serum folate ( P = 0.066) and VitB12 ( P = 0.017) levels for H-Y classification. The elevated folate level did correlate with greater decline in UPDRS-III score ( P = 0.023) and H-Y classification ( P = 0.003), whereas there was an obvious increase in ADL score ( P = 0.048). SII was negatively associated ( P < 0.001) with the ADL score. The three-dimensional drawing, combined with the effect of folate and VitB12 levels, showed that the lowest level of folate was associated with the lowest ADL score and the highest UPDRS-III score and H-Y classification. This study indicates that serum folate, VitB12 levels, and SII are significant factors influencing the motor performance status in patients with PD. SII is negatively associated with ADL. Elevated serum folate level correlates with mild motor impairment in patients with PD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Zhang, Gao, Nie, Liang, Zhang and Wang.)

Background: Nowadays, antidepressants still are the mainstay of treatment for depression in Parkinson's disease (PD) but some recent studies report that medication might aggravate motor symptoms in PD patients. This meta-analysis aims to assess the effect of non-pharmacological treatments for depression in patients with PD. Materials and Methods: Only randomized controlled trials (RCTs) were included. The participants were PD patients with comorbid depression (dPD). The interventions had the equivalent effect of non-pharmacological treatments alone compared with control(s). Scores of depression scale were selected as the primary outcome, while scores of Unified Parkinson's Disease Rating Scale part III and the incidence of side effects were the secondary outcome. The statistics were pooled and presented as weighted mean differences (WMDs), standardized mean differences (SMDs), or risk ratios (RRs) with their 95% confidence intervals (CIs). Results: Fifteen articles were eventually included; twelve studies reported on repetitive transcranial magnetic stimulation (rTMS) and three used cognitive behavioral therapy (CBT). Other interventions failed to have qualified studies. Our data indicated that both rTMS and CBT could significantly improve depression scores in a short term (SMD = -0.621, 95% CI [-0.964, -0.278]; SMD = -1.148, 95% CI [-1.498, -0.798], respectively). In addition, rTMS could alleviate motor symptom (WMD = -2.617, 95% CI [-4.183, -1.051]) and was relatively safe (RR = 1.054, 95% CI [0.698, 1.592]). Conclusion: Our data suggest that rTMS can safely alleviate depression and motor symptoms in dPD at least for a short period. Moreover, compared with clinical monitoring, CBT can improve depressive symptoms.