Urine metabolic phenotyping has been associated with the development of Parkinson’s disease (PD). However, few studies using a comprehensive metabolomics approach have investigated the correlation between changes in the urinary markers and the progression of clinical symptoms in PD. A comprehensive metabolomic study with robust quality control procedures was performed using gas chromatography - mass spectrometry (GC - MS) and liquid chromatography - mass spectrometry (LC - MS) to characterize the urinary metabolic phenotypes of idiopathic PD patients at three stages (early, middle and advanced) and normal control subjects, with the aim of discovering potential urinary metabolite markers for the diagnosis of idiopathic PD. Both GC-MS and LC-MS metabolic profiles of idiopathic PD patients differed significantly from those of normal control subjects. 18 differentially expressed metabolites were identified as constituting a unique metabolic marker associated with the progression of idiopathic PD. Related metabolic pathway variations were observed in branched chain amino acid metabolism, glycine derivation, steroid hormone biosynthesis, tryptophan metabolism, and phenylalanine metabolism. Comprehensive, successive metabolomic profiling revealed changes in the urinary markers associated with progression of idiopathic PD. This profiling relies on noninvasive sampling, and is complementary to existing clinical modalities.

Increasing evidence has shown that abnormal metabolic phenotypes in body fluids reflect the pathogenesis and pathophysiology of Parkinson's disease (PD). These body fluids include urine; however, the relationship between, specifically, urinary metabolic phenotypes and PD is not fully understood. In this study, urinary metabolites from a total of 401 clinical urine samples collected from 106 idiopathic PD patients and 104 normal control subjects were profiled by using high-performance liquid chromatography coupled to high-resolution mass spectrometry. Our study revealed significant correlation between clinical phenotype and urinary metabolite profile. Metabolic profiles of idiopathic PD patients differed significantly and consistently from normal controls, with related metabolic pathway variations observed in steroidogenesis, fatty acid beta-oxidation, histidine metabolism, phenylalanine metabolism, tryptophan metabolism, nucleotide metabolism, and tyrosine metabolism. In the fruit fly Drosophila melanogaster, the alteration of the kynurenine pathway in tryptophan metabolism corresponded with pathogenic changes in the alpha-synuclein overexpressed Drosophila model of PD. The results suggest that LC-MS-based urinary metabolomic profiling can reveal the metabolite signatures and related variations in metabolic pathways that characterize PD. Consistent PD-related changes across species may provide the basis for understanding metabolic regulation of PD at the molecular level.

Nonmotor symptoms (NMS) of Parkinson's disease (PD) have devastating impacts on both patients and their caregivers. Jiawei-Liujunzi Tang (JLT) has been used to treat some NMS of PD based on the Chinese medicine theory since Qing dynasty. Here we report a double-blind, randomized, placebo-controlled, add-on clinical trial aiming at evaluating the efficacy and safety of the JLT in treating NMS in PD patients. We randomly assigned 111 patients with idiopathic PD to receive either JLT or placebo for 32 weeks. Outcome measures were baseline to week 32 changes in Movement Disorder Society-Sponsored Revision of Unified PD Rating Scale (MDS-UPDRS) Parts I–IV and in NMS assessment scale for PD (NMSS). We observed improvements in the NMSS total score (p = 0.019), mood/cognition (p = 0.005), and reduction in hallucinations (p = 0.024). In addition, post hoc analysis showed a significant reduction in constipation (p < 0.001). However, there was no evidence of improvement in MDS-UPDRS Part I total score (p = 0.216) at week 32. Adverse events (AEs) were mild and comparable between the two groups. In conclusion, long-term administration of JLT is well tolerated and shows significant benefits in improving NMS including mood, cognition, and constipation.

Background There is a growing trend in the use of mobile health (mHealth) technologies in traditional Chinese medicine (TCM) and telemedicine, especially during the coronavirus disease (COVID-19) outbreak. Tongue diagnosis is an important component of TCM, but also plays a role in Western medicine, for example in dermatology. However, the procedure of obtaining tongue images has not been standardized and the reliability of tongue diagnosis by smartphone tongue images has yet to be evaluated. Objective The first objective of this study was to develop an operating classification scheme for tongue coating diagnosis. The second and main objective of this study was to determine the intra-rater and inter-rater reliability of tongue coating diagnosis using the operating classification scheme. Methods An operating classification scheme for tongue coating was developed using a stepwise approach and a quasi-Delphi method. First, tongue images (n=2023) were analyzed by 2 groups of assessors to develop the operating classification scheme for tongue coating diagnosis. Based on clinicians’ (n=17) own interpretations as well as their use of the operating classification scheme, the results of tongue diagnosis on a representative tongue image set (n=24) were compared. After gathering consensus for the operating classification scheme, the clinicians were instructed to use the scheme to assess tongue features of their patients under direct visual inspection. At the same time, the clinicians took tongue images of the patients with smartphones and assessed tongue features observed in the smartphone image using the same classification scheme. The intra-rater agreements of these two assessments were calculated to determine which features of tongue coating were better retained by the image. Using the finalized operating classification scheme, clinicians in the study group assessed representative tongue images (n=24) that they had taken, and the intra-rater and inter-rater reliability of their assessments was evaluated. Results Intra-rater agreement between direct subject inspection and tongue image inspection was good to very good (Cohen κ range 0.69-1.0). Additionally, when comparing the assessment of tongue images on different days, intra-rater reliability was good to very good (κ range 0.7-1.0), except for the color of the tongue body (κ=0.22) and slippery tongue fur (κ=0.1). Inter-rater reliability was moderate for tongue coating (Gwet AC2 range 0.49-0.55), and fair for color and other features of the tongue body (Gwet AC2=0.34). Conclusions Taken together, our study has shown that tongue images collected via smartphone contain some reliable features, including tongue coating, that can be used in mHealth analysis. Our findings thus support the use of smartphones in telemedicine for detecting changes in tongue coating.

Emerging evidence from Alzheimer’s disease (AD) patients suggests that reducing tau pathology can restore cognitive and memory loss. To reduce tau pathology, it is critical to find brain-permeable tau-degrading small molecules that are safe and effective. HDAC6 inhibition has long been considered a safe and effective therapy for tau pathology. Recently, we identified protopine as a dibenzazecine alkaloid with anti-HDAC6 and anti-AD activities. In this study, we synthesized and tested novel protopine derivatives for their pharmacological action against AD. Among them, bromo-protopine (PRO-Br) demonstrated a two-fold increase in anti-HDAC6 activity and improved anti-tau activities compared to the parent compound in both in vitro and in vivo AD models. Furthermore, molecular docking results showed that PRO-Br binds to HDAC6, with a ∆G value of −8.4 kcal/mol and an IC50 value of 1.51 µM. In neuronal cell lines, PRO-Br reduced pathological tau by inducing chaperone-mediated autophagy (CMA). In 3xTg-AD and P301S tau mice models, PRO-Br specifically decreased the pathogenic hyperphosphorylated tau clumps and led to the restoration of memory functions. In addition, PRO-Br treatment promoted the clearance of pathogenic tau by enhancing the expression of molecular chaperones (HSC70) and lysosomal markers (LAMP2A) via CMA in AD models. Our data strongly suggest that administration of the brain-permeable protopine derivative PRO-Br, could be a viable anti-tau therapeutic strategy for AD.