Gait disturbance gradually worsens as Parkinson's disease (PD) progresses, which significantly affects the quality of life of PD patients. Treadmill-based gait analysis systems can measure gait ...parameters including the dynamic center-of-pressure (COP) trajectory during ambulation. In this study, we hypothesized that altered dynamic COP changes are new gait characteristics for PD patients.
Dynamic COP parameters and classic spatiotemporal parameters were obtained for each patient using a treadmill-based system at the maximal comfortable treadmill speed (MCTS). We compared dynamic COP parameters between 44 PD patients and 31 controls, correlated these parameters with clinical and spatiotemporal data, and adjusted for age and MCTS to determine whether the parameters were independent from the treadmill speed. We also evaluated characteristics of COP parameters in relation to the more and less affected sides in PD patients.
During treadmill walking the length of the COP trajectory in the stance phase was decreased, an effect that was more prominent on the more affected side in PD patients. COP parameters related to this change were significantly altered in patients when compared to controls. Asymmetry of the COP trajectories compared between both feet was identified as a significant gait characteristic after adjusting for age and MCTS. The overlaid graphical display of dynamic COP trajectory in PD patients showed “distorted butterfly with asymmetric wing” feature.
Dynamic COP asymmetry provides a new and intuitive way to analyze gait abnormalities of PD patients. Further studies with prospective designs will substantiate the clinical usefulness of this feature of gait.
•Treadmill-based gait analysis was performed in Parkinson's disease (PD) patients.•Length of dynamic center-of-pressure (COP) trajectory during walking was decreased.•The effect was more prominent on the most affect side.•Asymmetry of COP trajectories between both feet was independent from treadmill speed.•These findings were easily recognizable in the overlaid graphical display.
Both genetic and environmental factors are important in the pathogenesis of Parkinson＇s disease. As α-synuclein is a major constituent of Lewy bodies, a pathologic hallmark of Parkinson＇s disease, ...genetic aspects of α-synuclein is widely studied. However, the influence of dietary factors such as quercetin on α-synuclein was rarely studied. Herein we aimed to study the neuroprotective role of quercetin against various toxins affecting apoptosis, autophagy and aggresome, and the role of quercetin on α-synuclein expression. PC12 cells were pre-treated with quercetin（100, 500, 1,000 μM） and then together with various drugs such as 1-methyl-4-phenylpyridinium（MPP＋; a free radical generator）, 6-hydroxydopamine（6-OHDA; a free radical generator）, ammonium chloride（an autophagy inhibitor）, and nocodazole（an aggresome inhibitor）. Cell viability was determined using a 3-4,5-dimethylthiazol-2-yl-2,5-diphenyltertazolium bromide（MTT） assay. Apoptosis was detected by annexin V-fluorescein isothiocyanate and propidium iodide through the use of fluorescence activated cell sorter. α-Synuclein expression was detected by western blot assay and immunohistochemistry. The role of α-synuclein was further studied by knocking out α-synuclein using RNA interference. Cell viability increased at lower concentrations（100 and 500 μM） of quercetin but decreased at higher concentration（1,000 μM）. Quercetin exerted neuroprotective effect against MPP＋, ammonium chloride and nocodazole at 100 μM. MPP＋ induced apoptosis was decreased by 100 μM quercetin. Quercetin treatment increased α-synuclein expression. However, knocking out α-synuclein exerted no significant effect on cell survival. In conclusion, quercetin is neuroprotective against toxic agents via affecting various mechanisms such as apoptosis, autophagy and aggresome. Because α-synuclein expression is increased by quercetin, the role of quercetin as an environmental factor in Parkinson＇s disease pathogenesis needs further investigation.
Although Parkinson’s disease (PD) is a representative neurodegenerative disorder and shows characteristic motor impediments, the pathophysiological mechanisms and treatment targets for PD have not ...yet been clearly identified. Since several tryptophan metabolites produced by gut microbiota could pass the blood–brain barrier and, furthermore, might influence the central nervous system, tryptophan metabolites within the indole, kynurenine, and serotonin metabolic pathways might be the most potent targets for PD development. Furthermore, most metabolites are circulated via the blood, play roles in and/or are metabolized via the host organs, and finally are excreted into the urine. Therefore, profiling the overall tryptophan metabolic pathways in urine samples of patients with PD is important to understanding the pathological mechanisms, finding biomarkers, and discovering therapeutic targets for PD. However, the development of profiling analysis based on tryptophan metabolism pathways in human urine samples is still challenging due to the wide physiological ranges, the varied signal response, and the structural diversity of tryptophan metabolites in complicated urine matrices. In this study, an LC–MS/MS method was developed to profile 21 tryptophan metabolites within the indole, kynurenine, and serotonin metabolic pathways in human urine samples using ion-pairing chromatography and multiple reaction monitoring determination. The developed method was successfully applied to urine samples of PD patients (n = 41) and controls (n = 20). Further, we investigated aberrant metabolites to find biomarkers for PD development and therapeutic targets based on the quantitative results. Unfortunately, most tryptophan metabolites in the urine samples did not present significant differences between control and PD patients, except for indole-3-acetic acid. Nonetheless, indole-3-acetic acid was reported for the first time for its aberrant urinary levels in PD patients and tentatively selected as a potential biomarker for PD. This study provides accurate quantitative results for 21 tryptophan metabolites in biological samples and will be helpful in revealing the pathological mechanisms of PD development, discovering biomarkers for PD, and further providing therapeutic targets for various PD symptoms. In the near future, to further investigate the relationship between gut microbial metabolites and PD, we will employ studies on microbial metabolites using plasma and stool samples from control and PD patients.
•A UPLC–MS/MS method was developed to profile a wide range of neurochemicals from the metabolic pathways of tyrosine, tryptophan, and glutamate in urine.•This is the first time in situ selective ...derivatization is applied to acidic and zwitterionic neurochemicals.•Acidic and basic neurochemicals were simultaneously detected in positive ion mode.•Appropriate MRM transition ions were chosen based on MS/MS fragmentations.•Clinical approach for the observation of metabolic alterations of neurochemicals in urine samples of Parkinson’s disease patients.
Development of a reliable analytical method of neurochemicals in biological fluids is important to discover potential biomarkers for the diagnosis, treatment and prognosis of neurological disorders. However, neurochemical profiling of biological samples is challenging because of highly different polarities between basic and acidic neurochemicals, low physiological levels, and high matrix interference in biological samples. In this study, an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method combined with in situ selective derivatization for comprehensive profiling of 20 neurochemicals in urine was developed for a wide range of neurochemicals. In situ selective derivatization greatly improved the peak capacity on a reversed-phase C18 column and sensitive mass detection in LC-ESI-MS/MS-positive ion mode due to reduction of the distinct physicochemical properties between acidic and basic neurochemicals. The MS/MS spectra of neurochemicals exhibited specific ions, such as losses of amine, methanol, or methyl formate molecules from protonated molecules, enabling selection of appropriate multiple reaction monitoring (MRM) ions for selective and sensitive detection. The developed method was validated in terms of linearity, limit of detection (LOD) and limit of quantification (LOQ), precision, accuracy, and recovery. The correlation coefficients (R2) of calibration curves were above 0.9961. The ranges of LODs and LOQs were 0.1–3.6ng/mL and 0.3–12.0ng/mL, respectively. The overall precision and accuracy were 0.52–16.74% and 82.26–118.17%, respectively. The method was successfully applied to simultaneously profile the metabolic pathways of tyrosine, tryptophan, and glutamate in Parkinson’s disease patient urine (PD, n=21) and control urine (n=10). Significant differences (P≤0.01) between two groups in the activity of phenylethanolamine N-methyltransferase (PNMT) and alcohol dehydrogenase (ADH) were observed. In conclusion, this method provides reliable quantification of a wide range of neurochemicals in human urine and would be helpful for finding biomarkers related to specific neuronal diseases.
Alpha-synuclein(αSyn) aggregates are definite pathological hallmarks of α-synucleinopathies. Seeding amplification assays (SAAs) have been developed to detect trace amounts of αSyn oligomers in ...vivo.. Herein, we assessed the diagnostic accuracy of the αSyn-SAAs across biospecimens, diagnostic references, methods, and subtypes.
A systematic literature search yielded 36 eligible studies for a meta-analysis of the sensitivity and specificity of αSyn-SAAs in patients with α-synucleinopathies(n = 2722) and controls(n = 2278). Pooled sensitivities and specificities with 95% confidence intervals (CIs) were calculated using bivariate random-effects models and a meta-regression analysis was performed.
The summary sensitivity and specificity of αSyn-SAAs positivity for the diagnosis of α-synucleinopathies were 0.88(95% CIs = 0.84–0.91) and 0.95(0.93–0.97), respectively. Two covariates (biospecimen and diagnostic reference) were significant in fitting the meta-regression model (likelihood-ratio test for sensitivity and specificity, p < 0.01, p = 0.01, respectively). Skin αSyn-SAAs exhibited the highest sensitivity 0.92(0.87–0.95), which was not different from that of cerebrospinal fluid (CSF)(0.90(0.86–0.93), p = 0.39). Olfactory mucosa αSyn-SAAs exhibited a lower sensitivity 0.64(0.49–0.76) than those of the other two specimens(p = 0.02, 0.01, compared to CSF and skin, respectively). Application of pathological diagnostic standards were associated with a higher specificity of αSyn-SAAs compared to clinical diagnosis (p < 0.01). The diagnostic sensitivity and specificity of CSF αSyn-SAAs were 0.91(0.87–0.94) and 0.96(0.93–0.98) for Lewy body disease, 0.90(0.79–0.95) and 0.96(0.90–0.98) for prodromal α-synucleinopathies, and 0.63(0.24–0.90) and 0.97(0.93–0.99) for multiple system atrophy.
αSyn-SAAs are promising in vivo detectors of abnormal αSyn aggregates and may aid the early diagnosis of α-synucleinopathies.
Objectives
This study aimed to compare susceptibility map-weighted imaging (SMwI) using various MRI machines (three vendors) with N-3-fluoropropyl-2-β-carbomethoxy-3-β-(4-iodophe nyl)nortropane (
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...F-FP-CIT) PET in the diagnosis of neurodegenerative parkinsonism in a multi-centre setting.
Methods
We prospectively recruited 257 subjects, including 157 patients with neurodegenerative parkinsonism, 54 patients with non-neurodegenerative parkinsonism, and 46 healthy subjects from 10 hospitals between November 2019 and October 2020. All participants underwent both SMwI and
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F-FP-CIT PET. SMwI was interpreted by two independent reviewers for the presence or absence of abnormalities in nigrosome 1, and discrepancies were resolved by consensus.
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F-FP-CIT PET was used as the reference standard. Inter-observer agreement was tested using Cohen’s kappa coefficient. McNemar’s test was used to test the agreement between the interpretations of SMwI and
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F-FP-CIT PET per participant and substantia nigra (SN).
Results
The inter-observer agreement was 0.924 and 0.942 per SN and participant, respectively. The diagnostic sensitivity of SMwI was 97.9% and 99.4% per SN and participant, respectively; its specificity was 95.9% and 95.2%, respectively, and its accuracy was 97.1% and 97.7%, respectively. There was no significant difference between the results of SMwI and
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F-FP-CIT PET (
p
> 0.05, for both SN and participant).
Conclusions
This study demonstrated that the high diagnostic performance of SMwI was maintained in a multi-centre setting with various MRI scanners, suggesting the generalisability of SMwI for determining nigrostriatal degeneration in patients with parkinsonism.
Key Points
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Susceptibility map-weighted imaging helps clinicians to predict nigrostriatal degeneration.
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The protocol for susceptibility map-weighted imaging can be standardised across MRI vendors.
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Susceptibility map-weighted imaging showed diagnostic performance comparable to that of dopamine transporter PET in a multi-centre setting with various MRI scanners.
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