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. Author manuscript; available in PMC: 2022 Apr 11.
Published in final edited form as: Neurosci Lett. 2021 Dec 28;769:136428. doi: 10.1016/j.neulet.2021.136428

Analysis of circulating metabolites to differentiate Parkinson’s disease and essential tremor

Elena A Ostrakhovitch 1, Eun-Suk Song 1, Jessica KA Macedo 2, Matthew S Gentry 2, Jorge E Quintero 3, Craig van Horne 3, Tritia R Yamasaki 1,4,5,*
PMCID: PMC8996687  NIHMSID: NIHMS1769418  PMID: 34971771

Abstract

Parkinson disease (PD) and essential tremor (ET) are two common adult-onset tremor disorders in which prevalence increases with age. PD is a neurodegenerative condition with progressive disability. In ET, neurodegeneration is not an established etiology. We sought to determine whether an underlying metabolic pattern may differentiate ET from PD. Circulating metabolites in plasma and cerebrospinal fluid were analyzed using gas chromatography-mass spectroscopy. There were several disrupted pathways in PD compared to ET plasma including glycolysis, tyrosine, phenylalanine, tyrosine biosynthesis, purine and glutathione metabolism. Elevated α-synuclein levels in plasma and CSF distinguished PD from ET. The perturbed metabolic state in PD was associated with imbalance in the pentose phosphate pathway, deficits in energy production, and change in NADPH, NADH and nicotinamide phosphoribosyltransferase levels. This work demonstrates significant metabolic differences in plasma and CSF of PD and ET patients.

Keywords: Parkinson’s disease, alpha-synuclein, metabolomic analysis, plasma, cerebrospinal fluid

1. Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by abnormal accumulation of aggregated forms of alpha-synuclein (α-syn) and nigrostriatal degeneration. Essential tremor (ET) is primarily as a tremor disorder, however there is evidence of gait ataxia and non-motor features as well [5, 23]. Although an association between ET and PD has been suggested, the majority of studies do not support a link between these conditions [1, 3, 26, 35].

Diagnosis of PD and ET is based on patient history and clinical presentation. In some cases, PD and ET demonstrate overlapping features that complicate clear diagnosis and can greatly affect treatment and prognosis [3, 35]. DaTSCAN™ (Ioflupane I123 injection) is an FDA-approved adjunct to aid diagnosis in unclear cases, although limitations on specificity must be considered. There is currently no biofluid-based test to distinguish these conditions.

Metabolic dysregulation contributes to the pathogenesis of neurodegenerative diseases, including PD [19, 29]. Reductions in cortical glucose metabolism are seen in newly diagnosed PD patients [14, 27]. Untargeted GC-MS metabolomic analysis permits robust high-throughput characterization of metabolites. Prior studies demonstrate increased metabolic stress in PD compared with controls, and alteration in lipid and glucose metabolism [17, 18, 22, 32, 36]. However, there are few studies evaluating the metabolic profile of ET and no studies comparing ET and PD metabolic parameters. In this study we compare cerebral CSF and blood from patients with PD and ET undergoing deep brain stimulation (DBS) surgery, and we identify metabolic pathways that discriminate PD from ET.

2. Materials and Methods

2.1. Patients and consent

Samples were collected during DBS surgery in PD (n=11) and ET (n=7) patients 55–78 years. Study group characteristics are delinated in Supplementary S1. Patients were followed by movement disorder specialists at Kentucky Neuroscience Institute and consented under an IRB-approved protocol at the point of candidacy for DBS as determined by clinical care standards.

2.2. Sample collection

After breaching dura and prior to placement of electrodes, cerebral CSF was collected by syringe with a sterile soft-tube catheter. Peripheral blood was collected during surgery (EDTA tubes) and plasma obtained within 30-minutes of collection by centrifugation at 2200g for 20 minutes at 4°C. CSF was centrifuged for 5 minutes. Samples were aliquoted and stored at −80°C.

2.3. Metabolite extraction/derivatization and GC-MS analysis

Extraction, derivatization and analysis protocols were described previously [34, 40]. Briefly, 30 μl of plasma and CSF were mixed with 1 ml of 100% ice cold methanol with 200 μM L-norvaline, placed on a cell disruptor (3000 rpm for 5 min), incubated on ice for 30 min, then centrifuged at 15000 rpm for 10 min. Supernatant containing polar metabolites was dried by SpeedVac. Pellets containing proteins were washed with 50% methanol, hydrolyzed with 3N HCl at 95°C for 2 hours and dried by SpeedVac. Samples were derivatized with methoxyamine and incubated 90 minutes at 30°C [13]. 20mg/ml N-methyl-trimethylsilyation (MSTFA) in pyridine was added. Samples were incubated for 20 min at 37°C. Derivatized samples were transferred to a v-shaped glass chromatography vial and analyzed by GC-MS on an Agilent GC with Agilent 5977A quadrupole MS instrument (Agilent). Sample (1 μL) was injected onto a GC column (30 m x 250 μm internal diameter, 0.25μm film thickness) in a 1:10 split mode. Initial temperature was 130°C, held for 4 min, rising at 6°C/min to 243°C, rising at 60°C/min to 280°C, held for 2 min. Full scan mode (m/z: 50–800) was used for target metabolite analysis. Relative abundances were normalized using internal standard L-norvaline, adjusted to protein input from pellet analysis. Results were analyzed with MetaboAnalyst 4.0.

2.4. NAD+ and NADP+/NADPH levels

Total plasma nicotinamide adenine dinucleotide (NADH) levels were assessed from 25 μl of plasma, using a NAD+/NADH kit (Cayman). Nicotinamide adenine dinucleotide phosphate (NADP+/NADPH) levels were assessed from 25 μl plasma using a NADP+/NADPH kit (Cell Biolabs). A 10KDa spin filter deproteinated plasma. Samples were analyzed in triplicate.

2.5. Dot blot assay

Bio-Dot Apparatus (Bio-Red, Hercules) was assembled with a pre-wet 0.4 μm nitrocellulose membrane. Plasma (25 μl) was diluted 2-fold and CSF (2 μl) was diluted 25-fold with TBS, and applied to the membrane (50 and 25 μl). Membranes were blocked for one hour at 25°C and probed with anti-α-synuclein Clone42 (BD 610787), rabbit monoclonal MJFR1 (Abcam, ab138501), rabbit monoclonal αSer129 (Abcam EP1536Y), and NAMPT (Invitrogen PA5–23198) antibody overnight at 4°C and detected with horseradish peroxidase-conjugated anti-rabbit/anti-mouse antibodies (Jackson ImmunoResearch) 1:10,000 or 1:5,000. Bands were visualized with SuperSignal West Pico Plus chemiluminescent substrate (Thermo Scientific) and ChemiDoc imaging system (Bio-Rad).

2.6. Data analysis/statistics

Statistical analyses utilized GraphPad Prism. Data are presented as mean±SD. Column analysis was performed using one-way ANOVA or t-test; p-values <0.05 were considered statistically significant.

3. Results

3.1. α-Synuclein in plasma and CSF

α-Synuclein in plasma and CSF samples from patients with PD and ET was measured by dot blot assay. PD plasma and CSF α-synuclein levels were significantly higher than in ET (Fig. 1A–D). Plasma levels of Ser129-phosphorylated α-synuclein (pSer129〈-syn) and the ratio of pSer129α-syn/total α-synuclein were significantly higher (p<0.01 and p<0.05) in PD than ET (Fig. 1E, F). There was no significant difference for pSer129α-syn in CSF (Fig. 1G, H).

Figure 1. Dot blot analysis of α-synuclein in plasma and CSF of PD and ET.

Figure 1.

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A. Dot blot of α-synuclein in plasma using MJFR1 and anti-α-synuclein, **p<0.01. B. Densitometric evaluation of plasma α-synuclein. C. Dot blot of α-synuclein level in CSF. D. Densitometric evaluation of α-synuclein in CSF, *p<0.05. E. Dot blot of pSer129α-syn in plasma using EP1536Y. F. Densitometric evaluation of pSer129α-syn in plasma. Relative intensity of pSer129α-syn to total α-synuclein detected by anti-α-synuclein,*p<0.05. G. Dot blot of pSer129α-syn in CSF. H. Densitometric evaluation of pSer129α-syn in CSF, p>0.01. All results are mean values ±S.D., Two-tailed student t-test P-value indicates statistical significance (PD vs. ET group).

3.2. Plasma metabolites

Polar metabolites in the plasma of PD and ET patients were assessed by GC-MS. Supervised clustering analysis was utilized to assess the overall metabolic profile in each cohort. Distinct clustering was observed in ET (red) and PD (green) samples (Fig. 2A). In plasma samples, 84 separate metabolite peaks were reliably identified in PD and ET groups (Supplementary S2). Of these, 11 metabolites were significantly different between PD and ET with a fold-change threshold Log2>2 (or <0.5) and t-test p-value threshold <0.05 (Fig. 2B). PD fatty acid metabolism was dysregulated with decreased plasma monosaturated palmitoleic acid (0.48-fold) and increased eicosapentaenoic acid (39.7-fold), an anti-inflammatory omega-3 polyunstaurated fatty acid (Fig. 2B).

Figure 2. Plasma metabolic changes in PD and ET.

Figure 2.

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A. The plasma Ortho (PLS-DA) score for ET (red) and PD (green). B. Fold change plots for PD and ET. C. Increased levels of sedoheptulose and sedoheptulose-7 phosphate in PD. D. Scheme showing the main metabolites in the pentose phosphate pathway which produces ribose-5P and NADPH in the oxidative branch. The non-oxidative branch is composed of reversible reactions which replenish the oxidative branch and feed into glycolysis. E. Plasma level of NADP+ and NADPH. F. Fold change of plasma ribose and uridine. All results are mean values ±S.D., *p < 0.05.

There were perturbations in the pentose phosphate pathway (PPP). The level of ribose was significantly downregulated (0.45-fold) and sedoheptulose was significantly upregulated (9.4-fold) in the PD group compared to ET (Fig. 2B). The increase in sedoheptulose and sedoheptulose-7-phosphate levels suggest dysfunction in the PPP (Fig. 2C). The PPP is divided into an oxidative branch and non-oxidative branch (Fig. 2D). The irreversible oxidative branch utilizes glucose 6-phosphate to produce ribose-5-phosphate and NADPH. Therefore, we measured NADPH and NADP+, which were significantly higher in PD plasma compared to ET (Fig. 2E), implying a more active oxidative arm of the PPP in PD. Consistent with activation of the non-oxidative segment of the PPP, the level of ribose was lower in PD than in ET plasma (Fig. 2F).

Plasma uridine was also significantly diminished (0.45-fold) (Fig. 2B, F) which could reflect ATP depletion and glucose hypometabolism since uridine homeostasis is tightly related to glucose homeostasis and lipid and amino acid metabolism [39].

3.3. Abnormal metabolic pathways in PD as compared to ET

We performed pathway enrichment analysis of metabolic pathways in plasma. Six metabolic pathways were identified as altered in PD: tyrosine metabolism; phenylalanine, tyrosine and tryptophan biosynthesis; quinone biosynthesis; glycolysis; and phenylalanine, purine and glutathione metabolism (Fig. 3A). We detected a higher plasma level of lactate and a 25% decrease of glutathione derivative cysteinylglycine, suggesting glutathione depletion in PD (Fig. 3B).

Figure 3. Elevated levels of plasma NADH and NAMPT in PD.

Figure 3.

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A. Pathway enrichment analysis as a function of log(p) and pathway impact factor for key metabolites in PD and ET plasma. B. Fold change in plasma lactate and cysteinylglycine. C. Plasma level of NADH. D. NAD is generated through the de novo pathway which converts tryptophan through the kynurenine pathway and the salvage pathway which recycles nicotinamide (NAM) and is a major source of NAD. NAM is converted to nicotinamide mononucleotide (NMN) by nicotinamide phosphoribosyltransferase (NAMPT). NAMN (nicotinic acid mononucleotide), NAAD (nicotinic acid adenine dinucleotide) and NADK (NAD+ kinase). E. Dot blot of NAMPT level in plasma. F. Densitometric evaluation of NAMPT. Analysis by two-tailed Student t-test. Statistical significance was obtained from two independent analyses (PD vs. ET group). All data are mean ±S.D., *p < 0.05, **p < 0.01.

Oxidative stress results from the failure to maintain redox homeostasis and is observed in PD [16]. The pyridine nucleotide redox system impacts the oxidative state and includies nicotinamide adenine dinucleotide (NADH/NAD+) [8, 28, 38]. We measured levels of NADH in the plasma samples of PD and ET patients. We detected a significant increase in NADH in PD plasma (Fig. 3C). Nicotinamide phosphoribosyltransferase (NAMPT) increases the NAD+ pool and plays an essential role in lipid and glucose metabolism (Fig. 3D). We found a significant increase in NAMPT in PD plasma samples (Fig. 3E–F) by dot blot analysis.

3.4. CSF metabolic profile

In CSF samples, supervised clustering analysis demonstrated clear separation between PD (green) and ET (red) (Fig. 4A) with 66 metabolite peaks identified in PD and ET patients (Supplementary S3). Eight metabolites were statistically altered in PD compared to ET. There were reduced levels of lactic acid (0.376-fold) and malic acid (0.43-fold), and increased levels of beta-hydroxyisovalerate (2.4-fold), monosaccharide (2.64-fold), urea (2-fold) and sucrose (1.7-fold) (Fig. 4B). Pathway enrichment analysis demonstrated alterations in glycine, serine and threonine metabolism, glyoxylate metabolism, and t-RNA biosynthesis in PD (Fig. 4C). Similar to plasma, purine and glutathione metabolism were altered in PD CSF. NAMPT levels did not show a statistically significant change in PD versus ET (Fig. 4D).

Figure 4. CSF metabolomic changes in PD and ET.

Figure 4.

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A. CSF analyzed by Ortho PLS-DA score plot with ET (red) and PD (green). B. Fold change plot is depicted. C. Pathway enrichment analysis identified perturbed metabolomic pathways in PD. D. Dot blot and densitometric analysis for NAMPT in CSF. Median values are increased in PD compared to ET CSF. Two-tailed Student t-test was not statistically significant. E. PD/ET ratio for selected metabolites in plasma and CSF.

The PD:ET ratio of specific metabolite concentrations in CSF and plasma showed significant variability (Fig. 4E). Pyruvate, urea, and dehydroascorbic acid levels showed elevated ratios, whereas oleic acid demonstrated reduction in PD versus ET in both CSF and plasma, implying concordance of the central and peripheral metabolomic states. Most striking was a significant elevation in eicosapentanoic acid and malic acid in plasma (but not CSF) in PD compared to ET. Discordance was also observed between CSF and plasma levels for lactate, serine, glycine, stearic and palmitic acid for PD versus ET which may imply a more specific CNS-based metabolomic change for those metabolites.

4. Discussion

PD is the most common age-related neurodegenerative movement disorder, whereas ET can occur at any age, but is most common in older people [12]. Although ET is a common neurological disorder, there are surprisingly few studies in this area. We detected higher levels of total α-syn and pSer129α-syn in PD plasma compared to ET. This is consistent with many studies investigating PD compared to controls [7, 9, 21]. We also detected higher levels of total α-syn in PD compared to ET in cerebral CSF samples. There was no significant difference in pSer129α-syn levels for PD and ET. Other groups have been unable to detect pSer129α-syn in PD CSF samples obtained through standard lumbar puncture [9]. In our study, we utilized cerebral CSF taken in proximity to the brain, which may have different characteristics than lumbar CSF. One limitation of our study, given the foundational nature, was the small sample size of PD and ET samples obtained. Another limitation, given cerebral CSF collection in the setting of brain surgery, was the lack of a similarly-treated control group, although we abstracted values found in literature for comparison (Supplementary S4).

Changes in metabolism are a key feature of neurodegenerative diseases like PD [27, 37]. ET patients show significant glucose hypermetabolism at the medulla, thalami, and cerebellar cortex, whereas PD patients exhibit cortical glucose hypometabolism [2, 15, 27]. Pathway enrichment analysis of plasma metabolites found that glycolysis was significantly altered in PD as compared to ET. We observed a trend toward lower glucose levels in PD plasma. Surprisingly, this change was not statistically significant. We found a decreased plasma ribose level in PD which also suggests glucose hypometabolism. It is possible that the advanced age of our participants results in an overall reduction in glycolysis [6, 24].

We found prominent dysregulation of the PPP in PD. Under oxidative stress conditions, which are characteristic of PD, glucose metabolism is rerouted from glycolysis through the oxidative segment of the PPP [20] and generates NADPH. In support of this, we found that NADPH and NADP+ levels were significantly higher in PD than ET. There was an increase in the level of sedoheptulose and sedoheptulose 7-phosphate, intermediates in the PPP, in PD samples.

Both NADP+/NADPH and NAD+/NADH are essential to the regulation of cellular metabolism, bioenergetic homeostasis, and redox balance. The level of NADH is relatively unaltered in normal aging [11]. We found a higher NADH level in PD plasma compared to ET. However, PD and ET NADH concentrations were significantly lower than those in healthy control subjects (0.44–2.88 μM) [31].

The increased level of NADH was associated with increased NAMPT in PD plasma compared to ET. NAMPT activates pro-inflammatory pathways. NAMPT inhibitors protect neurons against ischemic injury in vivo [4, 10, 41]. Our findings are consistent with studies that show upregulation of NAMPT mRNA in PD plasma [30]. There was no corresponding increase in CSF NAMPT in PD compared to ET which suggests that CSF NAMPT levels are generally low among this age group.

Tryptophan metabolism along the kynurenine pathway has been implicated in PD [18, 25]. The kynurenine pathway has been implicated in neuroinflammation in PD and leads to the production of NAD+ [33].

Increased plasma NADH suggests alteration in tryptophan metabolism and activation of the kynurenine pathway. We were unable to identify kynurenine metabolites with GC-MS. Liquid chromatography-mass spectrometry might allow analysis of tryptophan metabolites of the kynurenine pathway.

We compared the PD: ET ratio of metabolites in plasma and CSF. Specific metabolites did correlate, trending toward an increase or decrease in both plasma and CSF that might indicate a systemic effect. Other metabolites demonstrated discordance between plasma and CSF. In these cases, the CSF value is more likely to be reflective of a CNS-based dysfunction in PD.

5. Conclusions

This study was undertaken to determine whether the metabolic profile differs in PD and ET patients. We utilized plasma and CSF from patients with clinically-established movement disorders. We found that total and phosphorylated α-synuclein levels in plasma and cerebral CSF differentiate these cohorts. PD and ET have different metabolic profiles that are readily detected in plasma and CSF. Changes in metabolic profile were consistent with altered bioenergetics, dysregulation of the pentose phosphate pathway, increase in NADPH/NADH energy substrates, and elevation of NAMPT in PD vs ET plasma. This study provides insight into potential therapeutic targets for PD and suggests that differentiation of PD and ET may be possible through utilization of a carefully selected set of plasma-based markers.

Supplementary Material

1
2
3
4

Highlights.

  • Levels of α-synuclein in plasma and cerebral CSF distinguish PD from ET

  • Metabolic pathway profiles in plasma and CSF distinguish PD from ET

  • Increase in plasma NADH/NAMPT support pentose phosphate pathway dysregulation in PD

Acknowledgements

The authors would like to express our deep appreciation to our patients at the University of Kentucky Neuroscience Institute for their participation in this study. We are also grateful to Dr. Raymond Sun of the Neuroscience Department for constructive comments.

Funding

This study was supported by the University of Kentucky College of Medicine’s Brain and Epilepsy Alliance for Metabolism Research and a CCTS KL2 award TR000116 (T.R.Y). The research was also supported by the National Institute of Health (NIH) grants R35 NS116824 (M.S.G.). J.K.A.M. was supported by NIH/NCI training grant T32CA165990.

Abbreviations:

PD

Parkinson’s disease

ET

essential tremor

CSF

cerebrospinal fluid

MetPA

Metabolomic Pathway analysis

GC-MS

gas chromatography-mass spectrometry

MSTFA

N-methyl-N-trimethylsilyl-trifluoroacetamide

NADH

nicotinamide adenine dinucleotide

NADPH

nicotinamide adenine dinucleotide phosphate

NAMPT

Nicotinamide phosphoribosyltransferase

PUFA

polyunsaturated fatty acids

PPP

pentose phosphate pathway

NAMN

nicotinic acid mononucleotide

NAAD

nicotinic acid adenine dinucleotide

NAM

nicotinamide

NMN

nicotinamide mononucleotide

NADK

NAD+ kinase

Footnotes

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.

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References

  • [1].Adler CH, Shill HA, Beach TG, Essential tremor and Parkinson’s disease: lack of a link, Mov Disord 26 (2011) 372–377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [2].Albrecht F, Ballarini T, Neumann J, Schroeter ML, FDG-PET hypometabolism is more sensitive than MRI atrophy in Parkinson’s disease: A whole-brain multimodal imaging meta-analysis, Neuroimage Clin 21 (2019) 101594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [3].Algarni M, Fasano A, The overlap between Essential tremor and Parkinson disease, Parkinsonism Relat Disord 46 Suppl 1 (2018) S101–S104. [DOI] [PubMed] [Google Scholar]
  • [4].Audrito V, Messana VG, Deaglio S, NAMPT and NAPRT: Two Metabolic Enzymes With Key Roles in Inflammation, Front Oncol 10 (2020) 358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].Benito-Leon J, Essential tremor: a neurodegenerative disease?, Tremor Other Hyperkinet Mov (N Y) 4 (2014) 252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [6].Bi Q, Wang W, Niu N, Li H, Wang Y, Huang W, Chen K, Xu K, Zhang J, Chen Y, Wei D, Cui R, Shu N, Zhang Z, Relationship between the disrupted topological efficiency of the structural brain connectome and glucose hypometabolism in normal aging, Neuroimage 226 (2021) 117591. [DOI] [PubMed] [Google Scholar]
  • [7].Bougea A, Stefanis L, Paraskevas GP, Emmanouilidou E, Vekrelis K, Kapaki E, Plasma alpha-synuclein levels in patients with Parkinson’s disease: a systematic review and meta-analysis, Neurol Sci 40 (2019) 929–938. [DOI] [PubMed] [Google Scholar]
  • [8].Canto C, Menzies KJ, Auwerx J, NAD(+) Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus, Cell Metab 22 (2015) 31–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [9].Cariulo C, Martufi P, Verani M, Azzollini L, Bruni G, Weiss A, Deguire SM, Lashuel HA, Scaricamazza E, Sancesario GM, Schirinzi T, Mercuri NB, Sancesario G, Caricasole A, Petricca L, Phospho-S129 Alpha-Synuclein Is Present in Human Plasma but Not in Cerebrospinal Fluid as Determined by an Ultrasensitive Immunoassay, Front Neurosci 13 (2019) 889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [10].Chen CX, Huang J, Tu GQ, Lu JT, Xie X, Zhao B, Wu M, Shi QJ, Fang SH, Wei EQ, Zhang WP, Lu YB, NAMPT inhibitor protects ischemic neuronal injury in rat brain via anti- neuroinflammation, Neuroscience 356 (2017) 193–206. [DOI] [PubMed] [Google Scholar]
  • [11].Clement J, Wong M, Poljak A, Sachdev P, Braidy N, The Plasma NAD(+) Metabolome Is Dysregulated in “Normal” Aging, Rejuvenation Res 22 (2019) 121–130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [12].Deuschl G, Petersen I, Lorenz D, Christensen K, Tremor in the elderly: Essential and aging-related tremor, Mov Disord 30 (2015) 1327–1334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Fiehn O, Metabolomics by Gas Chromatography-Mass Spectrometry: Combined Targeted and Untargeted Profiling, Curr Protoc Mol Biol 114 (2016) 30 34 31–30 34 32. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [14].Firbank MJ, Yarnall AJ, Lawson RA, Duncan GW, Khoo TK, Petrides GS, O’Brien JT, Barker RA, Maxwell RJ, Brooks DJ, Burn DJ, Cerebral glucose metabolism and cognition in newly diagnosed Parkinson’s disease: ICICLE-PD study, J Neurol Neurosurg Psychiatry 88 (2017) 310–316. [DOI] [PubMed] [Google Scholar]
  • [15].Hallett M, Dubinsky RM, Glucose metabolism in the brain of patients with essential tremor, J Neurol Sci 114 (1993) 45–48. [DOI] [PubMed] [Google Scholar]
  • [16].Harish G, Mahadevan A, Srinivas Bharath MM, Shankar SK, Alteration in glutathione content and associated enzyme activities in the synaptic terminals but not in the non-synaptic mitochondria from the frontal cortex of Parkinson’s disease brains, Neurochem Res 38 (2013) 186–200. [DOI] [PubMed] [Google Scholar]
  • [17].Havelund JF, Heegaard NHH, Faergeman NJK, Gramsbergen JB, Biomarker Research in Parkinson’s Disease Using Metabolite Profiling, Metabolites 7 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [18].Heilman PL, Wang EW, Lewis MM, Krzyzanowski S, Capan CD, Burmeister AR, Du G, Escobar Galvis ML, Brundin P, Huang X, Brundin L, Tryptophan Metabolites Are Associated With Symptoms and Nigral Pathology in Parkinson’s Disease, Mov Disord 35 (2020) 2028–2037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Holscher C, Evidence for pathophysiological commonalities between metabolic and neurodegenerative diseases, Int Rev Neurobiol 155 (2020) 65–89. [DOI] [PubMed] [Google Scholar]
  • [20].Jiang T, Sun Q, Chen S, Oxidative stress: A major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson’s disease and Alzheimer’s disease, Prog Neurobiol 147 (2016) 1–19. [DOI] [PubMed] [Google Scholar]
  • [21].Lee PH, Lee G, Park HJ, Bang OY, Joo IS, Huh K, The plasma alpha-synuclein levels in patients with Parkinson’s disease and multiple system atrophy, J Neural Transm (Vienna) 113 (2006) 1435–1439. [DOI] [PubMed] [Google Scholar]
  • [22].Lewitt PA, Li J, Lu M, Beach TG, Adler CH, Guo L, Arizona Parkinson’s Disease C, 3-hydroxykynurenine and other Parkinson’s disease biomarkers discovered by metabolomic analysis, Mov Disord 28 (2013) 1653–1660. [DOI] [PubMed] [Google Scholar]
  • [23].Louis ED, Essential tremors: a family of neurodegenerative disorders?, Arch Neurol 66 (2009) 1202–1208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [24].Lowe VJ, Weigand SD, Senjem ML, Vemuri P, Jordan L, Kantarci K, Boeve B, Jack CR Jr., Knopman D, Petersen RC, Association of hypometabolism and amyloid levels in aging, normal subjects, Neurology 82 (2014) 1959–1967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [25].Ogawa T, Matson WR, Beal MF, Myers RH, Bird ED, Milbury P, Saso S, Kynurenine pathway abnormalities in Parkinson’s disease, Neurology 42 (1992) 1702–1706. [DOI] [PubMed] [Google Scholar]
  • [26].Ou R, Wei Q, Hou Y, Zhang L, Liu K, Lin J, Jiang Z, Song W, Cao B, Shang H, Association between positive history of essential tremor and disease progression in patients with Parkinson’s disease, Sci Rep 10 (2020) 21749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Peppard RF, Martin WR, Carr GD, Grochowski E, Schulzer M, Guttman M, McGeer PL, Phillips AG, Tsui JK, Calne DB, Cerebral glucose metabolism in Parkinson’s disease with and without dementia, Arch Neurol 49 (1992) 1262–1268. [DOI] [PubMed] [Google Scholar]
  • [28].Pollak N, Dolle C, Ziegler M, The power to reduce: pyridine nucleotides--small molecules with a multitude of functions, Biochem J 402 (2007) 205–218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Procaccini C, Santopaolo M, Faicchia D, Colamatteo A, Formisano L, de Candia P, Galgani M, De Rosa V, Matarese G, Role of metabolism in neurodegenerative disorders, Metabolism 65 (2016) 1376–1390. [DOI] [PubMed] [Google Scholar]
  • [30].Santiago JA, Littlefield AM, Potashkin JA, Integrative transcriptomic meta-analysis of Parkinson’s disease and depression identifies NAMPT as a potential blood biomarker for de novo Parkinson’s disease, Sci Rep 6 (2016) 34579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [31].Schwarzmann L, Pliquett RU, Simm A, Bartling B, Sex-related differences in human plasma NAD+/NADH levels depend on age, Biosci Rep 41 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].Shao Y, Li T, Liu Z, Wang X, Xu X, Li S, Xu G, Le W, Comprehensive metabolic profiling of Parkinson’s disease by liquid chromatography-mass spectrometry, Mol Neurodegener 16 (2021) 4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Sorgdrager FJH, Vermeiren Y, Van Faassen M, van der Ley C, Nollen EAA, Kema IP, De Deyn PP, Age- and disease-specific changes of the kynurenine pathway in Parkinson’s and Alzheimer’s disease, J Neurochem 151 (2019) 656–668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [34].Sun RC, Dukhande VV, Zhou Z, Young LEA, Emanuelle S, Brainson CF, Gentry MS, Nuclear Glycogenolysis Modulates Histone Acetylation in Human Non-Small Cell Lung Cancers, Cell Metab 30 (2019) 903–916 e907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [35].Tarakad A, Jankovic J, Essential Tremor and Parkinson’s Disease: Exploring the Relationship, Tremor Other Hyperkinet Mov (N Y) 8 (2018) 589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [36].Trupp M, Jonsson P, Ohrfelt A, Zetterberg H, Obudulu O, Malm L, Wuolikainen A, Linder J, Moritz T, Blennow K, Antti H, Forsgren L, Metabolite and peptide levels in plasma and CSF differentiating healthy controls from patients with newly diagnosed Parkinson’s disease, J Parkinsons Dis 4 (2014) 549–560. [DOI] [PubMed] [Google Scholar]
  • [37].Verdin E, NAD(+) in aging, metabolism, and neurodegeneration, Science 350 (2015) 1208–1213. [DOI] [PubMed] [Google Scholar]
  • [38].Xiao W, Wang RS, Handy DE, Loscalzo J, NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism, Antioxid Redox Signal 28 (2018) 251–272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [39].Yamamoto T, Koyama H, Kurajoh M, Shoji T, Tsutsumi Z, Moriwaki Y, Biochemistry of uridine in plasma, Clin Chim Acta 412 (2011) 1712–1724. [DOI] [PubMed] [Google Scholar]
  • [40].Young LEA, Brizzee CO, Macedo JKA, Murphy RD, Contreras CJ, DePaoli-Roach AA, Roach PJ, Gentry MS, Sun RC, Accurate and sensitive quantitation of glucose and glucose phosphates derived from storage carbohydrates by mass spectrometry, Carbohydr Polym 230 (2020) 115651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [41].Zhao B, Zhang M, Han X, Zhang XY, Xing Q, Dong X, Shi QJ, Huang P, Lu YB, Wei EQ, Xia Q, Zhang WP, Tang C, Cerebral ischemia is exacerbated by extracellular nicotinamide phosphoribosyltransferase via a non-enzymatic mechanism, PLoS One 8 (2013) e85403. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

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Supplementary Materials

1
NIHMS1769418-supplement-1.docx (27KB, docx)
2
NIHMS1769418-supplement-2.docx (17.1KB, docx)
3
NIHMS1769418-supplement-3.csv (16.6KB, csv)
4
NIHMS1769418-supplement-4.csv (10.6KB, csv)

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