Diagnosis of Parkinson’s Disease by A Metabolomics-Based Laboratory-Developed Test (LDT)

A laboratory-developed test (LDT) is a type of in vitro diagnostic test that is designed, manufactured and used in the same laboratory (i.e., an in-house test). In this study, a metabolomics-based LDT was developed. This test involves a blood plasma preparation, direct-infusion mass spectrometry analysis with a high-resolution mass spectrometer, alignment and normalization of mass peaks using original algorithms, metabolite annotation by a biochemical context-driven algorithm, detection of overrepresented metabolic pathways and results in a visualization in the form of a pathway names cloud. The LDT was applied to detect early stage Parkinson’s disease (PD)—the diagnosis of which currently requires great effort due to the lack of available laboratory tests. In a case–control study (n = 56), the LDT revealed a statistically sound pattern in the PD-relevant pathways. Usage of the LDT for individuals confirmed its ability to reveal this pattern and thus diagnose PD at the early-stage (1–2.5 stages, according to Hoehn and Yahr scale). The detection of this pattern by LDT could diagnose PD with a specificity of 64%, sensitivity of 86% and an accuracy of 75%. Thus, this LDT can be used for further widespread testing.

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Holistic Metabolomic Laboratory-Developed Test (LDT): Development and Use for the Diagnosis of Early-Stage Parkinson’s Disease

Metabolites ◽

10.3390/metabo11010014 ◽

2020 ◽

Vol 11 (1) ◽

pp. 14

Author(s):

Petr G. Lokhov ◽

Dmitry L. Maslov ◽

Steven Lichtenberg ◽

Oxana P. Trifonova ◽

Elena E. Balashova

Keyword(s):

Parkinson’S Disease ◽

Molecular Weight ◽

Parkinson's Disease ◽

High Resolution Mass Spectrometry ◽

Early Stage ◽

Disease Diagnosis ◽

The Body ◽

Low Molecular Weight ◽

Low Molecular Weight Compounds

A laboratory-developed test (LDT) is a type of in vitro diagnostic test that is developed and used within a single laboratory. The holistic metabolomic LDT integrating the currently available data on human metabolic pathways, changes in the concentrations of low-molecular-weight compounds in the human blood during diseases and other conditions, and their prevalent location in the body was developed. That is, the LDT uses all of the accumulated metabolic data relevant for disease diagnosis and high-resolution mass spectrometry with data processing by in-house software. In this study, the LDT was applied to diagnose early-stage Parkinson’s disease (PD), which currently lacks available laboratory tests. The use of the LDT for blood plasma samples confirmed its ability for such diagnostics with 73% accuracy. The diagnosis was based on relevant data, such as the detection of overrepresented metabolite sets associated with PD and other neurodegenerative diseases. Additionally, the ability of the LDT to detect normal composition of low-molecular-weight compounds in blood was demonstrated, thus providing a definition of healthy at the molecular level. This LDT approach as a screening tool can be used for the further widespread testing for other diseases, since ‘omics’ tests, to which the metabolomic LDT belongs, cover a variety of them.

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Retinal Morphological Changes during the Two Years of Follow-Up in Parkinson's Disease

10.21203/rs.3.rs-17217/v1 ◽

2020 ◽

Author(s):

Mahmut Atum ◽

Bekir Enes Demiryurek

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Rating Scale ◽

Early Stage ◽

Morphological Changes ◽

Fiber Layer ◽

Significant Difference ◽

Yahr Scale ◽

And Control

Abstract Background: The study aims to investigate the relationship between the progression of idiopathic Parkinson's disease (IPD) and retinal morphology. Methods: The study was carried out with 23 patients diagnosed with early-stage IPD (phases 1 and 2 of the Hoehn and Yahr scale) and 30 age-matched healthy controls. All patients were followed up at least two years, with 6-month intervals (initial, 6th month, 12th month, 18th month, and 24th month), and detailed neurological and ophthalmic examinations were performed at each follow-up. Unified Parkinson's Disease Rating Scale part III (UPDRS Part III) scores, Hoehn and Yahr (H&Y) scores, best-corrected visual acuity (BCVA), intraocular pressure (IOP) measurement, central macular thickness (CMT) and retinal nerve fiber layer (RNFL) thickness were analyzed at each visit. Results: The average age of the IPD and control groups was 43.96 ± 4.88 years, 44.53 ± 0.83 years, respectively. The mean duration of the disease in the IPD group was 7.48 ± 5.10 months at the start of the study (range 0-16). There was no statistically significant difference in BCVA and IOP values between the two groups during the two-year follow-up period (p> 0.05, p> 0.05, respectively). Average and superior quadrant RNFL thicknesses were statistically different between the two groups at 24 months and there was no significant difference between other visits (p = 0.025, p=0.034, p> 0.05, respectively). There was no statistically significant difference in CMT between the two groups during the follow-up period (p> 0.05). Conclusion: Average and superior quadrant RNFL thicknesses were significantly thinning with the progression of IPD.

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Metabolomics Fingerprint Induced by the Intranigral Inoculation of Exogenous Human Alpha-Synuclein Oligomers in a Rat Model of Parkinson’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21186745 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6745

Author(s):

Federica Murgia ◽

Luigi Atzori ◽

Ezio Carboni ◽

Maria Laura Santoru ◽

Aran Hendren ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dehydroascorbic Acid ◽

Alpha Synuclein ◽

Mass Spectrometry Analysis ◽

Substantia Nigra Pars Compacta ◽

Gas Chromatography Mass Spectrometry ◽

Serum Samples ◽

Spectrometry Analysis ◽

Metabolite Content

Parkinson’s disease (PD) is considered a synucleinopathy because of the intraneuronal accumulation of aggregated α-synuclein (αSyn). Recent evidence points to soluble αSyn-oligomers (αSynO) as the main cytotoxic species responsible for cell death. Given the pivotal role of αSyn in PD, αSyn-based models are crucial for the investigation of toxic mechanisms and the identification of new therapeutic targets in PD. By using a metabolomics approach, we evaluated the metabolic profile of brain and serum samples of rats infused unilaterally with preformed human αSynOs (HαSynOs), or vehicle, into the substantia nigra pars compacta (SNpc). Three months postinfusion, the striatum was dissected for striatal dopamine (DA) measurements via High Pressure Liquid Chromatography (HPLC) analysis and mesencephalon and serum samples were collected for the evaluation of metabolite content via gas chromatography mass spectrometry analysis. Multivariate, univariate and correlation statistics were applied. A 40% decrease of DA content was measured in the HαSynO-infused striatum as compared to the contralateral and the vehicle-infused striata. Decreased levels of dehydroascorbic acid, myo-inositol, and glycine, and increased levels of threonine, were found in the mesencephalon, while increased contents of fructose and mannose, and a decrease in glycine and urea, were found in the serum of HαSynO-infused rats. The significant correlation between DA and metabolite content indicated that metabolic variations reflected the nigrostriatal degeneration. Collectively, the metabolomic fingerprint of HαSynO-infused rats points to an increase of oxidative stress markers, in line with PD neuropathology, and provides hints for potential biomarkers of PD.

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Neuroprotection of Granulocyte Colony-Stimulating Factor for Early Stage Parkinson's Disease

Cell Transplantation ◽

10.3727/096368916x694247 ◽

2017 ◽

Vol 26 (3) ◽

pp. 409-416 ◽

Cited By ~ 7

Author(s):

Sheng-Tzung Tsai ◽

Sung-Chao Chu ◽

Shu-Hsin Liu ◽

Cheng-Yoong Pang ◽

Ting-Wen Hou ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Rating Scale ◽

Early Stage ◽

In Vivo Studies ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Elevated Liver Enzymes ◽

Stimulating Factor

Parkinson's disease (PD) is a slowly progressive neurodegenerative disease. Both medical and surgical choices provide symptomatic treatment. Granulocyte colony-stimulating factor (G-CSF), a conventional treatment for hematological diseases, has demonstrated its effectiveness in acute and chronic neurological diseases through its anti-inflammatory and antiapoptosis mechanisms. Based on previous in vitro and in vivo studies, we administered a lower dose (3.3 μg/kg) G-CSF injection for 5 days and six courses for 1 year in early-stage PD patients as a phase I trial. The four PD patient's mean unified PD rating scale motor scores in medication off status remained stable from 23 before the first G-CSF injection to 22 during the 2-year follow-up. 3,4-Dihydroxy-6-18F-fluoro-L-phenylalanine (18F-DOPA) positron emission tomography (PET) studies also revealed an annual 3.5% decrease in radiotracer uptake over the caudate nucleus and 7% in the putamen, both slower than those of previous reports of PD. Adverse effects included transient muscular–skeletal pain, nausea, vomiting, and elevated liver enzymes. Based on this preliminary report, G-CSF seems to alleviate disease deterioration for early stage PD patients. The effectiveness of G-CSF was possibly due to its amelioration of progressive dopaminergic neuron degeneration.

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Gender and Age Difference in Clinical Features and severity of Parkinson’s Disease: A Cross-Sectional Study in Southern Morocco

Archives of Neuroscience ◽

10.5812/ans.106239 ◽

2020 ◽

Vol 7 (3) ◽

Author(s):

Abderrahmane Achbani ◽

Sofiane Ait Wahmane ◽

Mohamed Elatiqi ◽

Hasnaa Sine ◽

Ahmed Kharbach ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Early Stage ◽

Experimental Studies ◽

Cross Sectional Study ◽

Age Difference ◽

Cross Sectional ◽

Gender And Age ◽

Initial Symptoms ◽

Yahr Scale

Background: Parkinson’s disease is the second most frequently reported neurodegenerative disease, behind Alzheimer’s disease. In Morocco, enough information are not available about its prevalence, progression, and characteristics, particularly in Southern regions of the country. Objectives: The current study aimed to investigate gender and age differences in the sociodemographic and clinical profile of Parkinson’s disease patients in southern Morocco. Methods: A cross-sectional descriptive study was conducted on a selected cohort of 180 patients, previously diagnosed with Parkinson’s. Results: The results showed that the onset of the disease was earlier in females compared to males. Besides, we found that the prevalence of rigidity symptoms was slightly higher in younger patients and in patients aged 61 to 70 years old, at the onset of the disease. Importantly, the results showed that the initial symptoms of males were different than females. According to the Hoehn and Yahr scale, the majority (82.6%) of patients of both genders were in the early stage of the disease. Additional statistical analyses, confirmed that the severity of the disease was strongly related to gender (P = 0.02). Conclusions: The findings confirmed that males and females had different clinical motor characteristics in the initial symptoms and progression of Parkinson’s disease. Nevertheless, experimental studies should be conducted to arrive at a real understanding of what underlies these differences.

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Biological Activity of the Tenebrionidae Beetle Antioxidant Complex in a Murine Neurotoxic Model of Parkinson's Disease

10.21203/rs.3.rs-806366/v1 ◽

2021 ◽

Author(s):

Vladimir Kovalzon ◽

Aleksandr Ambaryan ◽

Aleksandr Revishchin ◽

Galina Pavlova ◽

Ekaterina Rybalkina ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Biological Activity ◽

Early Stage ◽

Biologically Active ◽

Human Neuroblastoma ◽

Protein Nature ◽

And Control

Abstract We have previously shown that the aqueous extract of the Ulomoides dermestoides darking beetle (the Tenebrionidae family) biomass contains a powerful complex of antioxidant substances of protein and non-protein nature. Considering the crucial role of ROS in the development of neurodegeneration, we set out to test the biological activity of this extract in a mouse neurotoxic model of Parkinson's disease. The beetle extracts were administrated continuously with food and their effects on parkinsonism caused by twice injected defoliant paraquat to experimental mice was evaluated. The motor activity of the animals was analyzed in behavioral tests using a rotarod and a vertical pole. The number of tyrosine hydroxylase-immunopositive neurons in the ventral part of the substantia nigra of the midbrains of experimental and control mice was studied by immunohistochemistry. In the model in vitro system with SH-SY5Y human neuroblastoma, the effect of the extracts on cell proliferation was examined in the absence and presence of the neurotoxin MPP+. The isolation of biologically active substances from raw biomass using cavitation effects made it possible to obtain extracts with protective properties in the model of an early stage of Parkinson's disease used in this study.

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Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

Biomolecules ◽

10.3390/biom11070945 ◽

2021 ◽

Vol 11 (7) ◽

pp. 945

Author(s):

Antía Custodia ◽

Marta Aramburu-Núñez ◽

Clara Correa-Paz ◽

Adrián Posado-Fernández ◽

Ana Gómez-Larrauri ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Second Messengers ◽

Underlying Disease ◽

Mass Spectrometry Analysis ◽

Special Focus ◽

Ionization Mass ◽

Metabolic Dysfunction ◽

Spectrometry Analysis ◽

Cellular Processes

Ceramide is a bioactive sphingolipid involved in numerous cellular processes. In addition to being the precursor of complex sphingolipids, ceramides can act as second messengers, especially when they are generated at the plasma membrane of cells. Its metabolic dysfunction may lead to or be a consequence of an underlying disease. Recent reports on transcriptomics and electrospray ionization mass spectrometry analysis have demonstrated the variation of specific levels of sphingolipids and enzymes involved in their metabolism in different neurodegenerative diseases. In the present review, we highlight the most relevant discoveries related to ceramide and neurodegeneration, with a special focus on Parkinson’s disease.

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Preventive Activity of the Extract of the Darkling Beetle Ulomoides Dermestoides in the Diet of C57Bl/6JSTO Mice in a Neurotoxic Model of Parkinson's Disease

10.20944/preprints202105.0190.v2 ◽

2021 ◽

Author(s):

Vladimir M. Kovalzon ◽

Alexander V. Ambaryan ◽

Alexander V. Revishchin ◽

Galina V. Pavlova ◽

Ekaterina Y. Rybalkina ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Early Stage ◽

Biologically Active ◽

Human Neuroblastoma ◽

Delayed Effects ◽

Darkling Beetle ◽

Preventive Activity ◽

And Control

The effect of aqueous extracts of the biomass of the adult Ulomoides dermestoides beetle on the delayed effects of the defoliant paraquat causing parkinsonism in experimental mice was evaluated. The motor activity of the animals was analyzed in behavioral tests using a rotarod and a vertical pole. The number of tyrosine hydroxylase-immunopositive neurons in the ventral part of the substantia nigra of the midbrains of experimental and control mice was studied by immunohistochemistry. In the model in vitro system with SH-SY5Y human neuroblastoma, the effect of the extracts on cell proliferation was examined in the absence and presence of the neurotoxin MPP+. The isolation of biologically active substances from raw biomass using cavitation effects made it possible to obtain extracts with protective properties in the model of an early stage of Parkinson's disease used in this study.

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RasGRP1 is a causal factor in the development of l-DOPA–induced dyskinesia in Parkinson’s disease

Science Advances ◽

10.1126/sciadv.aaz7001 ◽

2020 ◽

Vol 6 (18) ◽

pp. eaaz7001 ◽

Cited By ~ 7

Author(s):

Mehdi Eshraghi ◽

Uri Nimrod Ramírez-Jarquín ◽

Neelam Shahani ◽

Tommaso Nuzzo ◽

Arianna De Rosa ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Molecular Mechanisms ◽

Involuntary Movement ◽

Mammalian Target Of Rapamycin ◽

Mass Spectrometry Analysis ◽

Therapeutic Effects ◽

Nucleotide Exchange ◽

Spectrometry Analysis ◽

Macaque Model

The therapeutic effects of l-3,4-dihydroxyphenylalanine (l-DOPA) in patients with Parkinson’s disease (PD) severely diminishes with the onset of abnormal involuntary movement, l-DOPA–induced dyskinesia (LID). However, the molecular mechanisms that promote LID remain unclear. Here, we demonstrated that RasGRP1 [(guanine nucleotide exchange factor (GEF)] controls the development of LID. l-DOPA treatment rapidly up-regulated RasGRP1 in the striatum of mouse and macaque model of PD. The lack of RasGRP1 in mice (RasGRP1−/−) dramatically diminished LID without interfering with the therapeutic effects of l-DOPA. Besides acting as a GEF for Ras homolog enriched in the brain (Rheb), the activator of the mammalian target of rapamycin kinase (mTOR), RasGRP1 promotes l-DOPA–induced extracellular signal-regulated kinase (ERK) and the mTOR signaling in the striatum. High-resolution tandem mass spectrometry analysis revealed multiple RasGRP1 downstream targets linked to LID vulnerability. Collectively, the study demonstrated that RasGRP1 is a critical striatal regulator of LID.

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