Idiopathic Rapid Eye Movement Sleep Behavior Disorder (iRBD) Shares Similar Fecal Short-Chain Fatty Acid Alterations with Multiple System Atrophy (MSA) and Parkinson's Disease (PD).

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is considered as a prodromal stage of synucleinopathies. Fecal short-chain fatty acid (SCFA) changes in iRBD and the relationships with synucleinopathies have never been investigated. OBJECTIVES: To investigate fecal SCFA changes among iRBD, multiple system atrophy (MSA), and Parkinson's disease (PD), and evaluate their relationships. METHODS: Fecal SCFAs and gut microbiota were measured in 29 iRBD, 42 MSA, 40 PD, and 35 normal controls (NC) using gas chromatography-mass spectrometry and 16S rRNA gene sequencing. RESULTS: Compared with NC, fecal SCFA levels (propionic, acetic, and butyric acid) were lower in iRBD, MSA, and PD. Combinations of these SCFAs could differentiate NC from iRBD (AUC 0.809), MSA (AUC 0.794), and PD (AUC 0.701). Decreased fecal SCFAs were associated with the common reducing SCFA-producing gut microbiota in iRBD, MSA, and PD. CONCLUSIONS: iRBD shares similar fecal SCFA alterations with MSA and PD, and the combination of these SCFAs might be a potential synucleinopathies-related biomarker. © 2024 International Parkinson and Movement Disorder Society.

PENCIL imaging: A novel approach for neuromelanin sensitive MRI in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is associated with the loss of neuromelanin (NM) and increased iron in the substantia nigra (SN). Magnetization transfer contrast (MTC) is widely used for NM visualization but has limitations in brain coverage and scan time. This study aimed to develop a new approach called Proton-density Enhanced Neuromelanin Contrast in Low flip angle gradient echo (PENCIL) imaging to visualize NM in the SN. METHODS: This study included 30 PD subjects and 50 healthy controls (HCs) scanned at 3T. PENCIL and MTC images were acquired. NM volume in the SN pars compacta (SNpc), normalized image contrast (Cnorm), and contrast-to-noise ratio (CNR) were calculated. The change of NM volume in the SNpc with age was analyzed using the HC data. A group analysis compared differences between PD subjects and HCs. Receiver operating characteristic (ROC) analysis and area under the curve (AUC) calculations were used to evaluate the diagnostic performance of NM volume and CNR in the SNpc. RESULTS: PENCIL provided similar visualization and structural information of NM compared to MTC. In HCs, PENCIL showed higher NM volume in the SNpc than MTC, but this difference was not observed in PD subjects. PENCIL had higher CNR, while MTC had higher Cnorm. Both methods revealed a similar pattern of NM volume in SNpc changes with age. There were no significant differences in AUCs between NM volume in SNpc measured by PENCIL and MTC. Both methods exhibited comparable diagnostic performance in this regard. CONCLUSIONS: PENCIL imaging provided improved CNR compared to MTC and showed similar diagnostic performance for differentiating PD subjects from HCs. The major advantage is PENCIL has rapid whole-brain coverage and, when using STAGE imaging, offers a one-stop quantitative assessment of tissue properties.

MRI index of glymphatic system mediates the influence of locus coeruleus on cognition in Parkinson's disease.

INTRODUCTION: Although locus coeruleus (LC) has been demonstrated to play a critical role in the cognitive function of Parkinson's disease (PD), the underlying mechanism has not been elucidated. The objective was to investigate the relationship among LC degeneration, cognitive performance, and the glymphatic function in PD. METHODS: In this retrospective study, 71 PD subjects (21 with normal cognition; 29 with cognitive impairment (PD-MCI); 21 with dementia (PDD)) and 26 healthy controls were included. All participants underwent neuromelanin-sensitive magnetic resonance imaging (NM-MRI) and diffusion tensor image scanning on a 3.0 T scanner. The brain glymphatic function was measured using diffusion along the perivascular space (ALPS) index, while LC degeneration was estimated using the NM contrast-to-noise ratio of LC (CNRLC). RESULTS: The ALPS index was significantly lower in both the whole PD group (P = 0.04) and the PDD subgroup (P = 0.02) when compared to the controls. Similarly, the CNRLC was lower in the whole PD group (P < 0.001) compared to the controls. In the PD group, a positive correlation was found between the ALPS index and both the Montreal Cognitive Assessment (MoCA) score (r = 0.36; P = 0.002) and CNRLC (r = 0.26; P = 0.03). Mediation analysis demonstrated that the ALPS index acted as a significant mediator between CNRLC and the MoCA score in PD subjects. CONCLUSION: The ALPS index, a neuroimaging marker of glymphatic function, serves as a mediator between LC degeneration and cognitive function in PD.

Life and disease status of patients with Parkinson's disease during and after zero-COVID in China: an online survey.

BACKGROUND: Little is known about the impact of the COVID-19 pandemic on patients with Parkinson's disease (PD) at different stages of the pandemic. This study aims to assess the lives and disease status of PD patients during the zero-COVID policy period and after ending the zero-COVID policy. METHODS: This multicenter cross-sectional study included two online surveys among PD patients in China, from May 30 to June 30 in 2022 and from January 1 to February 28 in 2023, respectively. The survey questionnaires contained four sections: (1) status of COVID-19 infection; (2) impact on motor and non-motor symptoms; (3) impact on daily and social lives; and (4) impact on PD disease management. RESULTS: A total of 1764 PD patients participated in the first online survey, with 200 patients having lockdown experience and 3 being COVID-19-positive (0.17%). In addition, 537 patients participated in the second online survey, with 467 patients having COVID-19 infection (86.96%). (1) During zero-COVID, all of the COVID-19-positive patients had mild symptoms of COVID-19 and no death was reported. After zero-COVID, 83.51% of the COVID-19-positive patients had mild symptoms. The overall death rate and inpatient mortality rate of COVID-19-positive PD patients were 3.21% and 30.00%, respectively. (2) During zero-COVID, 49.43% of PD patients reported worsening of PD-related symptoms (lockdown vs. unlockdown, 60.50% vs. 48.02%, P = 0.0009). After zero-COVID, 54.93% of PD patients reported worsening of PD-related symptoms (COVID-19 positive vs. COVID-19 negative, 59.31% vs. 25.71%, P < 0.0001). (3) During zero-COVID, 62.36% of patients felt worried, and 'limited outdoor activities' (55.39%) was the top reason for mental health problems. After zero-COVID, 59.03% of patients felt worried, with 'poor health' (58.10%) being the top reason. The PD patients tended to change their daily activities from offline to online, and their economic and caregiver burdens increased both during and after zero-COVID. (4) Most PD patients would like to choose online rehabilitation during (69.56%) and after zero-COVID (69.27%). The demand for online medication purchasing also increased during (47.00%) and after zero-COVID (26.63%). CONCLUSIONS: The COVID-19 pandemic aggravated the motor and non-motor symptoms of PD patients either during or after the zero-COVID policy period. The PD patients also experienced prominent mental health problems, changes in daily activities, and increases in economic and caregiver burdens. The COVID-19 pandemic has changed ways of PD management with increasing demands for online medication purchasing and rehabilitation.

Tai Chi improves non-motor symptoms of Parkinson's disease: One-year randomized controlled study with the investigation of mechanisms.

BACKGROUND: Tai Chi was found to improve motor symptoms in Parkinson's disease (PD). Whether long-term Tai Chi training could improve non-motor symptoms (NMS) and the related mechanisms were unknown. OBJECTIVE: To investigate Tai Chi's impact on non-motor symptoms in PD and related mechanisms. METHODS: 95 early-stage PD patients were recruited and randomly divided into Tai Chi (N = 32), brisk walking (N = 31), and no-exercise groups (N = 32). All subjects were evaluated at baseline, 6 months, and 12 months within one-year intervention. Non-motor symptoms (including cognition, sleep, autonomic symptoms, anxiety/depression, and quality of life) were investigated by rating scales. fMRI, plasma cytokines and metabolomics, and blood Huntingtin interaction protein 2 (HIP2) mRNA levels were detected to observe changes in brain networks and plasma biomarkers. RESULTS: Sixty-six patients completed the study. Non-motor functions assessed by rating scales, e.g. PD cognitive rating scale (PDCRS) and Epworth Sleepiness scale (ESS), were significantly improved in the Tai Chi group than the control group. Besides, Tai Chi had advantages in improving NMS-Quest and ESS than brisk walking. Improved brain function was seen in the somatomotor network, correlating with improved PDCRS (p = 0.003, respectively). Downregulation of eotaxin and upregulation of BDNF demonstrated a positive correlation with improvement of PDCRS and PDCRS-frontal lobe scores (p ≤ 0.037). Improvement of energy and immune-related metabolomics (p ≤ 0.043), and elevation of HIP2 mRNA levels (p = 0.003) were also found associated with the improvement of PDCRS. CONCLUSIONS: Tai Chi improved non-motor symptoms in PD, especially in cognition and sleep. Enhanced brain network function, downregulation of inflammation, and enhanced energy metabolism were observed after Tai Chi training.

Enhancing Nigrosome-1 Sign Identification via Interpretable AI using True Susceptibility Weighted Imaging.

BACKGROUND: Nigrosome 1 (N1), the largest nigrosome region in the ventrolateral area of the substantia nigra pars compacta, is identifiable by the "N1 sign" in long echo time gradient echo MRI. The N1 sign's absence is a vital Parkinson's disease (PD) diagnostic marker. However, it is challenging to visualize and assess the N1 sign in clinical practice. PURPOSE: To automatically detect the presence or absence of the N1 sign from true susceptibility weighted imaging by using deep-learning method. STUDY TYPE: Prospective. POPULATION/SUBJECTS: 453 subjects, including 225 PD patients, 120 healthy controls (HCs), and 108 patients with other movement disorders, were prospectively recruited including 227 males and 226 females. They were divided into training, validation, and test cohorts of 289, 73, and 91 cases, respectively. FIELD STRENGTH/SEQUENCE: 3D gradient echo SWI sequence at 3T; 3D multiecho strategically acquired gradient echo imaging at 3T; NM-sensitive 3D gradient echo sequence with MTC pulse at 3T. ASSESSMENT: A neuroradiologist with 5 years of experience manually delineated substantia nigra regions. Two raters with 2 and 36 years of experience assessed the N1 sign on true susceptibility weighted imaging (tSWI), QSM with high-pass filter, and magnitude data combined with MTC data. We proposed NINet, a neural model, for automatic N1 sign identification in tSWI images. STATISTICAL TESTS: We compared the performance of NINet to the subjective reference standard using Receiver Operating Characteristic analyses, and a decision curve analysis assessed identification accuracy. RESULTS: NINet achieved an area under the curve (AUC) of 0.87 (CI: 0.76-0.89) in N1 sign identification, surpassing other models and neuroradiologists. NINet localized the putative N1 sign within tSWI images with 67.3% accuracy. DATA CONCLUSION: Our proposed NINet model's capability to determine the presence or absence of the N1 sign, along with its localization, holds promise for enhancing diagnostic accuracy when evaluating PD using MR images. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Relationships Between Rapid Eye Movement Sleep Behavior Disorder and Parkinson's Disease: Indication from Gut Microbiota Alterations.

Rapid eye movement sleep behavior disorder (RBD) has a close relationship with Parkinson's disease (PD) and was even regarded as the most reliable hallmark of prodromal PD. RBD might have similar changes in gut dysbiosis to PD, but the relationship between RBD and PD in gut microbial alterations is rarely studied. In this study, we aim to investigate whether there were consistent changes between RBD and PD in gut microbiota, and found some specific biomarkers in RBD that might indicate phenoconversion to PD. Alpha-diversity showed no remarkable difference and beta-diversity showed significant differences based on the unweighted (R = 0.035, P = 0.037) and weighted (R = 0.0045, P = 0.008) UniFrac analysis among idiopathic RBD (iRBD), PD with RBD, PD without RBD and normal controls (NC). Enterotype distribution indicated iRBD, PD with RBD and PD without RBD were Ruminococcus-dominant while NC were Bacteroides-dominant. 7 genera (4 increased: Aerococcus, Eubacterium, Gordonibacter and Stenotrophomonas, 3 decreased: Butyricicoccus, Faecalibacterium and Haemophilus) were consistently changed in iRBD and PD with RBD. Among them, 4 genera (Aerococcus, Eubacterium, Butyricicoccus, Faecalibacterium) remained distinctive in the comparison between PD with RBD and PD without RBD. Through clinical correlation analysis, Butyricicoccus and Faecalibacterium were found negatively correlated with the severity of RBD (RBD-HK). Functional analysis showed iRBD had similarly increased staurosporine biosynthesis to PD with RBD. Our study indicates that RBD had similar gut microbial changes to PD. Decreased Butyricicoccus and Faecalibacterium might be potential hallmarks of phenoconversion of RBD to PD.

Effect of long-term Tai Chi training on Parkinson's disease: a 3.5-year follow-up cohort study.

BACKGROUND: Tai Chi has shown beneficial effects on the motor and non-motor symptoms of Parkinson's disease (PD), but no study has reported the effect of long-term Tai Chi training. OBJECTIVE: To examine whether long-term Tai Chi training can maintain improvement in patients with PD. METHODS: Cohorts of patients with PD with Tai Chi training (n=143) and patients with PD without exercise as a control group (n=187) were built from January 2016. All subjects were assessed at baseline and in November 2019, October 2020 and June 2021. A logarithmic linear model was used to analyse rating scales for motor and non-motor symptoms. The need to increase antiparkinsonian therapies was presented as a Kaplan-Meier plot and as a box plot. The bootstrap method was used to resample for statistical estimation. RESULTS: Tai Chi training reduced the annual changes in the deterioration of the Unified Parkinson's Disease Rating Scale and delayed the need for increasing antiparkinsonian therapies. The annual increase in the levodopa equivalent daily dosage was significantly lower in the Tai Chi group. Moreover, patients benefited from Tai Chi training in motor symptoms, non-motor symptoms and complications. CONCLUSION: Tai Chi training has a long-term beneficial effect on PD, with an improvement in motor and non-motor symptoms and reduced complications. TRIAL REGISTRATION NUMBER: NCT05447975.

Clinical safety and efficacy of allogenic human adipose mesenchymal stromal cells-derived exosomes in patients with mild to moderate Alzheimer's disease: a phase I/II clinical trial.

Background: There have been no effective treatments for slowing or reversing Alzheimer's disease (AD) until now. Growing preclinical evidence, including this study, suggests that mesenchymal stem cells-secreted exosomes (MSCs-Exos) have the potential to cure AD. Aims: The first three-arm, drug-intervention, phase I/II clinical trial was conducted to explore the safety and efficacy of allogenic human adipose MSCs-Exos (ahaMSCs-Exos) in patients with mild to moderate AD. Methods: The eligible subjects were assigned to one of three dosage groups, intranasally administrated with ahaMSCs-Exos two times per week for 12 weeks, and underwent follow-up visits at weeks 16, 24, 36 and 48. Results: No adverse events were reported. In the medium-dose arm, Alzheimer's Disease Assessment Scale-Cognitive section (ADAS-cog) scores decreased by 2.33 (1.19) and the basic version of Montreal Cognitive Assessment scores increased by 2.38 (0.58) at week 12 compared with baseline levels, indicating improved cognitive function. Moreover, the ADAS-cog scores in the medium-dose arm decreased continuously by 3.98 points until week 36. There were no significant differences in altered amyloid or tau deposition among the three arms, but hippocampal volume shrank less in the medium-dose arm to some extent. Conclusions: Intranasal administration of ahaMSCs-Exos was safe and well tolerated, and a dose of at least 4×108 particles could be selected for further clinical trials. Trial registration number: NCT04388982.

Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets.

Microglia activation is observed in various neurodegenerative diseases. Recent advances in single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified microglia in specific states correlate with pathological hallmarks and are associated with specific functions. Microglia both exert protective function by phagocytosing and clearing pathological protein aggregates and play detrimental roles due to excessive uptake of protein aggregates, which would lead to microglial phagocytic ability impairment, neuroinflammation, and eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes microglia into a pro-inflammatory phenotype and accelerates disease progression. Microglia also act as a mobile vehicle to propagate protein aggregates. Extracellular vesicles released from microglia and autophagy impairment in microglia all contribute to pathological progression and neurodegeneration. Thus, enhancing microglial phagocytosis, reducing microglial-mediated neuroinflammation, inhibiting microglial exosome synthesis and secretion, and promoting microglial conversion into a protective phenotype are considered to be promising strategies for the therapy of neurodegenerative diseases. Here we comprehensively review the biology of microglia and the roles of microglia in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies and Huntington's disease. We also summarize the possible microglia-targeted interventions and treatments against neurodegenerative diseases with preclinical and clinical evidence in cell experiments, animal studies, and clinical trials.

Ketogenic diet alleviates cognitive dysfunction and neuroinflammation in APP/PS1 mice via the Nrf2/HO-1 and NF-κB signaling pathways.

Alzheimer's disease is a progressive neurological disorder characterized by cognitive decline and chronic inflammation within the brain. The ketogenic diet, a widely recognized therapeutic intervention for refractory epilepsy, has recently been proposed as a potential treatment for a variety of neurological diseases, including Alzheimer's disease. However, the efficacy of ketogenic diet in treating Alzheimer's disease and the underlying mechanism remains unclear. The current investigation aimed to explore the effect of ketogenic diet on cognitive function and the underlying biological mechanisms in a mouse model of Alzheimer's disease. Male amyloid precursor protein/presenilin 1 (APP/PS1) mice were randomly assigned to either a ketogenic diet or control diet group, and received their respective diets for a duration of 3 months. The findings show that ketogenic diet administration enhanced cognitive function, attenuated amyloid plaque formation and proinflammatory cytokine levels in APP/PS1 mice, and augmented the nuclear factor-erythroid 2-p45 derived factor 2/heme oxygenase-1 signaling pathway while suppressing the nuclear factor-kappa B pathway. Collectively, these data suggest that ketogenic diet may have a therapeutic potential in treating Alzheimer's disease by ameliorating the neurotoxicity associated with Aß-induced inflammation. This study highlights the urgent need for further research into the use of ketogenic diet as a potential therapy for Alzheimer's disease.

Predicting the Prognosis of Multiple System Atrophy Using Cluster and Principal Component Analysis.

BACKGROUND: Multiple system atrophy (MSA) is an intractable neurodegenerative disorder with poorly understanding of prognostic factors. OBJECTIVE: The purpose of this retrospective longitudinal study was to explore the main predictors of survival of MSA patients with new clinical subtypes based on cluster analysis. METHODS: A total of 153 Chinese MSA patients were recruited in our study. The basic demographic data and motor and nonmotor symptoms were assessed. Cluster and principal component analysis (PCA) were used to eliminate collinearity and search for new clinical subtypes. The multivariable Cox regression was used to find factors associated with survival in MSA patients. RESULTS: The median survival time from symptom onset to death (estimated using data from all patients by Kaplan-Meier analysis) was 6.3 (95% CI = 6.1-6.7) years. The survival model showed that a shorter survival time was associated with motor principal component (PC)1 (HR = 1.71, 95% CI: 1.26-2.30, p < 0.001) and nonmotor PC3 (HR = 1.68, 95% CI: 1.31-2.10, p < 0.001) through PCA. Four clusters were identified: Cluster 1 (mild), Cluster 2 (mood disorder-dominant), Cluster 3 (axial symptoms and cognitive impairment-dominant), and Cluster 4 (autonomic failure-dominant). Multivariate Cox regression indicated that Cluster 3 (HR = 4.15, 95% CI: 1.73-9.90, p = 0.001) and Cluster 4 (HR = 4.18, 95% CI: 1.73-10.1, p = 0.002) were independently associated with shorter survival time. CONCLUSION: More serious motor symptoms, axial symptoms such as falls and dysphagia, orthostatic hypotension, and cognitive impairment were associated with poor survival in MSA via PCA and cluster analysis.

Evaluation of Nocturnal Symptoms in Chinese Parkinson's Disease Patients Based on the PDSS-2 Scale: A Multicenter Cross-Sectional Study.

BACKGROUND: Nocturnal symptoms have a significant effect on the quality of life in Parkinson's disease (PD) patients. OBJECTIVE: This study aimed to investigate the prevalence and associated factors of nocturnal symptoms in Chinese PD patients. METHODS: This multicenter cross-sectional study included 1,500 patients with primary PD from 18 centers in China was carried out between February 2019 and February 2020. Questionnaires including Parkinson's disease sleep scale 2 (PDSS-2), Parkinson's disease questionnaire 8 (PDQ-8), Beck depression inventory (BDI), and generalized anxiety disorder scale 7 (GAD-7) were used to assess nocturnal symptoms, quality of life, depression, and anxiety. RESULTS: Among 1,500 Chinese PD patients, 576 (38.4%) reported nocturnal symptoms. Of them, 59.2% were older than 65 years. The PDQ-8 total score was higher in patients with nocturnal symptoms (p < 0.01). Moderate and severe depression was reported more often in patients with nocturnal symptoms (p < 0.01), and the occurrence and severity of anxiety were higher as well (p < 0.01). Longer disease duration and higher Hoehn-Yahr (HY) stage were independently associated with nocturnal symptoms (p < 0.01). Education level, depression, disease course, HY stage, and nocturnal symptoms were related to the quality of life in Chinese PD patients (p < 0.01). CONCLUSION: Our study found that 38.4% of Chinese PD patients have nocturnal symptoms, even in early and mid-stage PD. Nocturnal symptoms were associated with worse quality of life and higher incidences of depression and anxiety. Nocturnal symptoms should be included in the assessment and care plan, especially in patients with longer disease courses and higher HY stages.

Association of fecal short-chain fatty acids with clinical severity and gut microbiota in essential tremor and its difference from Parkinson's disease.

Diagnosis of essential tremor (ET) at an early stage can be difficult, especially when distinguishing it from healthy controls (HCs) and Parkinson's disease (PD). Recently, stool sample analysis of gut microbiota and its metabolites provides new ways to detect novel biomarkers for neurodegenerative diseases. Short-chain fatty acids (SCFAs), as the main metabolites of gut microbiota, were reduced in the feces of PD. However, fecal SCFAs in ET have never been investigated. We aimed to investigate the fecal SCFA levels in ET, assess their relationships with clinical symptoms and gut microbiota, and identify their potential diagnostic abilities. Fecal SCFAs and gut microbiota in 37 ET, 37 de novo PD and 35 HC were measured. Constipation, autonomic dysfunction and tremor severity were evaluated by scales. ET had lower fecal propionic, butyric and isobutyric acid levels than HC. Combined propionic, butyric and isobutyric acid distinguished ET from HC with an AUC of 0.751 (95% CI: 0.634-0.867). ET had lower fecal isovaleric and isobutyric acid levels than PD. Isovaleric and isobutyric acid differentiated ET from PD with an AUC of 0.743 (95% CI: 0.629-0.857). Fecal propionic acid was negatively correlated with constipation and autonomic dysfunction. Isobutyric and isovaleric acid were negatively associated with tremor severity. Lowered fecal SCFAs were related to a decreased abundance of Faecalibacterium and Catenibacterium in ET. In conclusion, fecal SCFAs were decreased in ET and correlated with clinical severity and gut microbiota changes. Fecal propionic, butyric, isobutyric and isovaleric acid might be potential diagnostic and differential diagnostic biomarkers for ET.

An automatic interpretable deep learning pipeline for accurate Parkinson's disease diagnosis using quantitative susceptibility mapping and T1-weighted images.

Parkinson's disease (PD) diagnosis based on magnetic resonance imaging (MRI) is still challenging clinically. Quantitative susceptibility maps (QSM) can potentially provide underlying pathophysiological information by detecting the iron distribution in deep gray matter (DGM) nuclei. We hypothesized that deep learning (DL) could be used to automatically segment all DGM nuclei and use relevant features for a better differentiation between PD and healthy controls (HC). In this study, we proposed a DL-based pipeline for automatic PD diagnosis based on QSM and T1-weighted (T1W) images. This consists of (1) a convolutional neural network model integrated with multiple attention mechanisms which simultaneously segments caudate nucleus, globus pallidus, putamen, red nucleus, and substantia nigra from QSM and T1W images, and (2) an SE-ResNeXt50 model with an anatomical attention mechanism, which uses QSM data and the segmented nuclei to distinguish PD from HC. The mean dice values for segmentation of the five DGM nuclei are all >0.83 in the internal testing cohort, suggesting that the model could segment brain nuclei accurately. The proposed PD diagnosis model achieved area under the the receiver operating characteristic curve (AUCs) of 0.901 and 0.845 on independent internal and external testing cohorts, respectively. Gradient-weighted class activation mapping (Grad-CAM) heatmaps were used to identify contributing nuclei for PD diagnosis on patient level. In conclusion, the proposed approach can potentially be used as an automatic, explainable pipeline for PD diagnosis in a clinical setting.

Locus coeruleus and substantia nigra neuromelanin magnetic resonance imaging differentiates Parkinson's disease and essential tremor.

BACKGROUND: Differential diagnosis of essential tremor (ET) and Parkinson's disease (PD) can still be a challenge in clinical practice. These two tremor disorders may have different pathogenesis related to the substantia nigra (SN) and locus coeruleus (LC). Characterizing neuromelanin (NM) in these structures may help improve the differential diagnosis. METHODS: Forty-three subjects with tremor-dominant PD (PDTD), 31 subjects with ET, and 30 age- and sex-matched healthy controls were included. All subjects were scanned with NM magnetic resonance imaging (NM-MRI). NM volume and contrast measures for the SN and contrast for the LC were evaluated. Logistic regression was used to calculate predicted probabilities by using the combination of SN and LC NM measures. The discriminative power of the NM measures in detecting subjects with PDTD from ET was assessed with a receiver operative characteristic curve, and the area under the curve (AUC) was calculated. RESULTS: The NM contrast-to-noise ratio (CNR) of the LC, the NM volume, and CNR of the SN on the right and left sides were significantly lower in PDTD subjects than in ET subjects or healthy controls (all P < 0.05). Furthermore, when combining the best model constructed from the NM measures, the AUC reached 0.92 in differentiating PDTD from ET. CONCLUSION: The NM volume and contrast measures of the SN and contrast for the LC provided a new perspective on the differential diagnosis of PDTD and ET, and the investigation of the underlying pathophysiology.

Early changes of fecal short-chain fatty acid levels in patients with mild cognitive impairments.

AIMS: To compare the fecal levels of short-chain fatty acids (SCFAs) in patients with mild cognitive impairment (MCI) and normal controls (NCs) and to examine whether fecal SCFAs could be used as the biomarker for the identification of patients with MCI. To examine the relationship between fecal SCFAs and amyloid-ß (Aß) deposition in the brain. METHODS: A cohort of 32 MCI patients, 23 Parkinson's disease (PD) patients, and 27 NC were recruited in our study. Fecal levels of SCFAs were measured using chromatography and mass spectrometry. Disease duration, ApoE genotype, body mass index, constipation, and diabetes were evaluated. To assess cognitive impairment, we used the Mini-Mental Status Examination (MMSE). To assess brain atrophy, the degree of medial temporal atrophy (MTA score, Grade 0-4) was measured by structural MRI. Aß positron emission tomography with 18 F-florbetapir (FBP) was performed in seven MCI patients at the time of stool sampling and in 28 MCI patients at an average of 12.3 ± 0.4 months from the time of stool sampling to detect and quantify Aß deposition in the brain. RESULTS: Compared with NC, MCI patients had significantly lower fecal levels of acetic acid, butyric acid, and caproic acid. Among fecal SCFAs, acetic acid performed the best in discriminating MCI from NC, achieved an AUC of 0.752 (p = 0.001, 95% CI: 0.628-0.876), specificity of 66.7%, and sensitivity of 75%. By combining fecal levels of acetic acid, butyric acid, and caproic acid, the diagnostic specificity was significantly improved, reaching 88.9%. To better verify the diagnostic performance of SCFAs, we randomly assigned 60% of participants into training dataset and 40% into testing dataset. Only acetic acid showed significantly difference between these two groups in the training dataset. Based on the fecal levels of acetic acid, we achieved the ROC curve. Next, the ROC curve was evaluated in the independent test data and 61.5% (8 in 13) of patients with MCI, and 72.7% (8 in 11) of NC could be identified correctly. Subgroup analysis showed that reduced fecal SCFAs in MCI group were negatively associated with Aß deposition in cognition-related brain regions. CONCLUSION: Reductions in fecal SCFAs were observed in patients with MCI compared with NC. Reduced fecal SCFAs were negatively associated with Aß deposition in cognition-related brain regions in MCI group. Our findings suggest that gut metabolite SCFAs have the potential to serve as early diagnostic biomarkers for distinguishing patients with MCI from NC and could serve as potential targets for preventing AD.

Regulation of Hsa-miR-4639-5p expression and its potential role in the pathogenesis of Parkinson's disease.

Decreased DJ-1 protein impairs antioxidative activity of neurons and plays an important role in the occurrence of Parkinson's disease (PD). We have previously identified hsa-miR-4639-5p as the post-transcriptional regulator of DJ-1. Increased expression of hsa-miR-4639-5p reduced DJ-1 level and increased oxidative stress leading to neuronal death. Therefore, understanding the detailed mechanisms by which hsa-miR-4639-5p expression is regulated will not only facilitate diagnosis but also inform the pathogenesis of PD. We examined hsa-miR-4639-5 in either the plasma or exosomes derived from the central nervous system (CNS) neurons of PD patients and healthy controls. We showed that CNS-derived exosomes gave rise to the increased plasma hsa-miR-4639-5p in PD patients, pointing to hsa-miR-4639-5p dysregulation in the brain of PD patients. Using a dual-luciferase assay and a CRISPR-Cas9 system, we identified a core promoter of hsa-miR-4639 (-560 to -275 upstream the transcriptional starting site) of the gene for myosin regulatory light chain interacting protein. A polymorphism in the core promoter (rs760632 G>A) could enhance hsa-miR-4639-5p expression and increase PD risk. Furthermore, using MethylTarget™ assay, ChIP-qPCR, and specific inhibitors, we demonstrated that hsa-miR4639-5p expression was regulated by HDAC11-mediated histone acetylation but not DNA methylation/demethylation. Taken together, our study provides evidence that hsa-miR-4639-5p is a potential diagnostic marker and therapeutic target for PD. Interventions targeting hsa-miR-4639-5p might represent a novel therapy to promote healthy aging.