|Year : 2020 | Volume
| Issue : 3 | Page : 91-98
A Systematic Review on Urinary Biomarkers for Early Diagnosis of Alzheimer’s Disease (AD)
P. Rani, S. Vivek, S. Maheswar Ram
Department of Biotechnology, PSG College of Technology, Coimbatore, Tamil Nadu, India
|Date of Submission||04-Feb-2020|
|Date of Decision||08-Mar-2020|
|Date of Acceptance||31-Mar-2020|
|Date of Web Publication||20-Aug-2020|
Professor P. Rani
Department of Biotechnology, PSG College of Technology, Coimbatore, 641004
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Alzheimer’s disease (AD) is a neurodegenerative disease that commonly affects the older population whose symptoms are only visible during the later stage which renders the available treatment ineffective. Our study attempts to provide a solution to this problem by identifying urinary biomarkers that could be used in the first-line screening of a larger population for AD before analysing with more sophisticated blood and CSF based biomarkers, which provide high sensitivity on comparison. A systematic review was performed using the keywords “Alzheimer”, “urine”, “biomarkers” and “metabolomics” following the PRISMA criteria, to identify urinary biomarkers for the early diagnosis of Alzheimer’s disease. From the performed study, three metabolites were identified namely 5-hydroxy indole acetic acid, L-arginine and allantoin as biomarkers whose level was altered in AD samples compared to controls. In AD, 5-hydroxy indole acetic acid level was downregulated in urine probably because of the extensive serotonergic denervation that has been observed in the AD brain. Increased levels of L-arginine in the brain which act as a precursor to nitric oxide due to the action of NO synthase might potentially lead to neurotoxicity when present in excess, and is also known to be in synergy with ROS. Increased levels of allantoin in urine is due to the action of increased ROS in the system reacting with uric acid. Here, we provide an overview of all the reported metabolites obtained from the search, by discussing their influence in AD pathology. This study identified three metabolites in urine that could function as potential biomarkers for AD based on significant changes observed between disease and control samples, along with its recurrence and commonality in different models namely mice and human. However, longitudinal and cross-sectional follow-up studies are required for the validation of these biomarkers.
Keywords: Alzheimer’s disease, early diagnosis, metabolomics, urinary biomarkers
|How to cite this article:|
Rani P, Vivek S, Ram SM. A Systematic Review on Urinary Biomarkers for Early Diagnosis of Alzheimer’s Disease (AD). Int J Nutr Pharmacol Neurol Dis 2020;10:91-8
|How to cite this URL:|
Rani P, Vivek S, Ram SM. A Systematic Review on Urinary Biomarkers for Early Diagnosis of Alzheimer’s Disease (AD). Int J Nutr Pharmacol Neurol Dis [serial online] 2020 [cited 2021 Jan 18];10:91-8. Available from: https://www.ijnpnd.com/text.asp?2020/10/3/91/292679
| Introduction|| |
Dementia refers to the severe changes occurring in the brain that causes memory loss. Globally, around 50 million people are affected by dementia and about 10 million new cases are being reported annually. In India, nearly 4 million people are affected by some form of dementia. The prevalence of Alzheimer’s disease (AD) is high among the aging population with dementia. In the United States, about 5.8 million Americans are affected by Alzheimer’s dementia. AD is a chronic neurodegenerative disease that affects cognitive ability such as memory, thinking and reasoning.
Several factors are involved in the disease etiology which include amyloid β(Aβ) accumulation, oxidative stress, tau phosphorylation, lipid dysregulation, mitochondrial dysfunction, and inflammation. In the case of Aβ accumulation, the β-amyloid proteins get adsorbed to the receptors of neuronal cells and get internalized to form amyloid fibrils which result in senile plaque formation.
Under physiological conditions, lower levels of ROS is regarded as a mode of signal transduction which allows for any adaptation to occur in the system, based on the changes occurring in the surrounding oxidative environment. However, under oxidative stress, excess production of reactive oxygen species (ROS) occurs which causes denaturation of all biomolecules due to pathological redox reactions. The abnormal hyperphosphorylation of normal tau proteins, which is also a consequence of increased ROS, polymerizes the paired helical filaments (PHF) with straight filaments (SF) resulting in the formation of neurofibrillary tangles in AD.
Mitochondrial dysfunction and lipid dysregulation are constantly associated with Aβ plaque formation of AD. Amyloid Beta (Aβ) monomers are generated through the cleavage of Aβ precursor protein by α‐, β‐, and γ‐secretases. Mitochondrial dysfunction occurs also in oxidative stress resulting in the production of lipid peroxidation product 4‐hydroxynonenal, which covalently modifies the γ‐secretase complex and contribute to amplified secretase activity. This results in accelerated Aβ accumulation, thereby resulting in neurodegeneration.
AD can be progressively categorized into three stages namely preclinical, mild cognitive impairment (MCI) and dementia. Currently, there are no effective drugs/treatments available to reverse or halt the progression of AD. The early and predictive diagnosis of AD is the paramount importance which could be made possible using biomarkers.
Biomarkers are measurable changes associated with the disease. The most common biomarkers associated with the diagnosis of AD are cerebral spinal fluid (CSF) and blood-based biomarkers. The identification of these biomarkers in AD patients involves invasive, expensive and time-consuming methods. An alternative biomarker for diagnosing AD could be obtained from the urine.
Unlike blood, which is stable because of homeostasis mechanisms, urine can accumulate many kinds of changes that could be exploited as a potential biomarker, particularly in the earlier stages of most diseases. Also, urine is a preferred resource for biomarker discovery since it can be non-invasively collected. The collection, storage, and post-treatment processes of plasma samples can adversely affect proteomics analysis and biomarker studies. In addition, the high abundance of plasma proteins provides a major constraint to plasma proteomics and subsequent biomarker screening.
Urinary biomarkers can help in providing first-line screening of diseases for larger population, which can be confirmed through sophisticated and more-sensitive CSF and blood-based biomarker analyses with high reliability. Due to the lack of any homeostasis mechanism, urine might reflect pathological changes, especially in the early stages of the neurodegenerative diseases which was studied in transgenic mouse models. This paper aims to systematically review the scientific literature and identify the potential urinary biomarkers for early diagnosis of AD.
| Materials and Methods|| |
In the study, a comprehensive electronic search was performed in PubMed and Alzforum databases using the Boolean expression (Alzheimer) AND (urine) AND (biomarker) AND (metabolomics). We searched for scientific papers without any time limit, as this area of study is relatively new. Those studies that were not based on diagnostic biomarkers were filtered. This procedure was repeated till December 2019, before the finalization of the manuscript, to include papers published on this subject until the submission of the present work. We also performed hand-searches of references cited in the associated studies to identify additional contributions.
No restrictions were imposed regarding language or country of publication. Assessment of eligibility was preliminary based on the analysis of the title and abstract of selected papers, followed by full-text screening. Biomarkers were grouped according to three major types namely oxidative stress associated, amyloid plaque formation associated and energy metabolism associated biomarkers. PRISMA criteria were followed for the systematic review [Figure 1].
|Figure 1 PRISMA flowchart − inclusion and exclusion criteria application in the systematic study.|
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The inclusion and exclusion criteria of the studies are described as:
- Inclusion: All articles on urinary biomarkers and the associated metabolomic profiling linked to the early diagnosis of Alzheimer’s disease were included in the study.
- Exclusion: All results and articles associated with therapy primarily, those studies focussed on only the analytical techniques, review articles and ones that do not focus on the early diagnosis (i.e. preclinical and mild cognitive impairment cases) were excluded from the systematic study.
| Results|| |
As depicted in [Figure 1], 30 records were identified from the electronic searches performed across PubMed (under “Best Match” conditions) and Alzforum databases. The duplicate entries were then removed and 19 unique records were identified. From the obtained entries, five listings based on webinars and seminars were removed. On reviewing the full-text articles of 14 records, and performing an assessment on their eligibility, the exclusion criteria were applied to filter off the review articles, studies based on analytical techniques, studies focused on treatments and those articles that do not involve the early diagnosis of dementia, AD or MCI. As a result, the data for this study were extracted from a total of six articles.
The studies analyzed were compiled and represented in [Table 1]. The table contains various information such as authors (with the year of publication), sample number, country, platforms used, list of reported metabolites and our classification of the reported biomarkers based on the pathological involvement. All six studies with 26 potential biomarkers have been analyzed to arrive at the link between the brain and the urine. From the analysis, we could arrive at the possible involvement of these metabolites in their corresponding metabolic pathways which could influence AD pathogenesis.
|Table 1 Summary of studies identified from the systematic review of literature|
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| Discussion|| |
The development of reliable biomarkers that measures the risk, presence, and progression of the disease is one of the main goals and challenges in the research of neurodegenerative diseases, especially in AD. The existence of neuroimaging possibilities, CSF and blood-based biomarkers have helped in monitoring brain changes associated with its structures and inflammatory processes, but do not promote easily obtainable results from a larger population or with any inexpensive testing procedures. , Therefore, the need for biomarkers which not only provides an opportunity for in-depth investigation of the changes related to the early diagnosis of AD pathology but also serve as non-invasive alternatives with easier sample collection and processing procedures are required. This study attempts to aid in achieving that goal by identifying potential urinary biomarkers that could help in the large-scale screening of AD and attempt to establish a relationship between the metabolites and the associated metabolic pathways through the available literature.
Methodologies involved in biomarker metabolite analysis in this review include various techniques such as 1H-NMR, LC-MS, LC-MS/MS, UHPLC, UPLC and GC-MS which renders the data pooling more complex for quantitative comparisons and further analysis. However, the relative changes observed in the metabolite status in AD samples with respect to control samples, have been considered as criteria for metabolite selection. The major metabolites identified were relevant to the metabolism of tryptophan, arginine, tyrosine, cysteine and choline metabolisms [Figure 2]. The metabolites were grouped into the following AD pathological processes namely, oxidative stress, amyloid plaque formation, and energy metabolism associated biomarkers [Figure 3].
|Figure 2 Metabolic disturbances related to metabolites leading to neurodegeneration and AD pathology.|
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|Figure 3 Graphical representation of the framework used to identify urinary biomarkers for AD pathology − i) Study organisms; ii) analytical techniques; iii) mechanisms associated with AD pathology.|
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Biomarkers associated with oxidative stress
Fukuhara et al., have reported three metabolites namely 3-hydroxykynurenine, homogentisate and allantoin, which are relevant to oxidative stress, a major pathological process for AD.  3-hydroxy kynurenine is associated with the catabolic pathway of tryptophan metabolism.,, It acts as a potential glutamate receptor antagonist and also results in the accumulation of ROS  which could be due to the production of quinolinic acid. Quinolinic acid, under normal conditions, helps in the synthesis of NAD+ but under pathophysiological concentrations can lead to neurotoxicity and dysfunction, by various mechanisms. An increase in 3-hydroxy kynurenine in urine levels in AD samples, in turn, indicates decreased neurotransmitter activity in the brain, due to its antagonistic nature.
Homogentisate is an oxidative stress associated biomarker which is associated with alkaptonuria,, also an intermediate in the catabolism of tyrosine and phenylalanine pathways. It reacts with the ROS present in the system and forms benzoquinone acetate, under oxidative stress conditions. Increased levels of homogentisate in the urine of AD patients indicated decreased neurotransmitter production. It also reduces the amount of maleylacetoacetate, which is involved in the energy metabolism process of the brain.
Allantoin, a product of purine metabolism and is also known to play a role in the neuronal cell proliferation of the hippocampal region of the brain. An increase in allantoin levels in urine could indicate the increase in ROS in the system. Being the end product of the uric acid metabolism, significant changes from any non-enzymatic process could be detected using this biomarker with higher reliability in comparison to the other biomarkers.
A decrease in the concentration of N1-acetylspermidine in the urine from AD individuals was reported in the biochemical study. N1-acetylspermidine is an anti-oxidant belonging to the polyamine family, which plays an important role in stabilizing the cell membranes, cell growth, and differentiation and in the biosynthesis of several important molecules.
Acetyl-L-carnitine (ALC) is an antioxidant intrinsically containing unique neuro-modulatory and neurotrophic properties, which may play an important role in counteracting AD processes. Acetyl-L-carnitine is also neuroprotective when administered at supraphysiologic concentrations, and so their decreased concentration in urine could indicate an increased risk of AD. A study suggests that ALC might possess other important functions besides antioxidant activities such as neuroprotection in their involvement with the nervous system.
Arginosuccinic acid is a precursor for arginine in the urea cycle or citrulline-nitric oxide cycle. Arginine, being an excitatory amino acid, its increased levels in urine could indicate the arginine-excessive transshipment and conduction which could in turn damage nerve cells and result in AD.L-glutamine, the non-essential amino acid amide of glutamic acid, may act as a protectant in stress responses  and could affect the brain functioning under increased levels of the same. A study has reported that variations in glutamatergic signaling, including the fluctuations in the expression of glutamate transporters and its enzymes could lead to neuronal dysfunction of AD.
5-L-glutamyl glycine is an excitatory amino acid receptor antagonist with a structure similar to γ −aminobutyrate, which can reduce the release of glutamic acid by acting as a postsynaptic blocker and antagonizing glutamate toxicity thereby protecting the nerve cells from anoxic neuronal death. The low level of this inhibitory amino acid in the brain may cause memory disorders in AD patients. Increased level of 5-L-glutamyl glycine in the urine of AD patients might indicate decreased GABA in AD patients, leading to memory dysfunction.
Dimethyl arginine is involved in arginine metabolism. From arginine, nitrous oxide (NO) is produced by NO synthase which not only results in oxidative damage, but also causes neurotoxicity along with ROS in the system. When the level of arginine increases, the amount of NO produced would increase resulting in oxidative stress development, which would in-turn cause damages to the neuronal cell. This is usually prevented by dimethylarginine. There are two types of dimethylarginine namely symmetric dimethyl arginine (SDMA) and asymmetric dimethylarginine (ADMA) which act as nitrous oxide (NO) inhibitors. The ADMA inhibits NO production by inhibiting NO synthase enzyme. The SDMA inhibits NO production by competitively inhibiting the L-arginine uptake by the cell. When this metabolite is downregulated, the NO production increases and results in oxidative damage.
4-guanidinobutanoic acid is produced by the transfer of the guanidine group from arginine to gamma-aminobutyric acid through transamination., This metabolite causes neuronal damage due to the development of oxidative stress. 1-methyladenosine and 5’-deoxyadenosine are formed through purine metabolism. They are the modified nucleotides due to oxidative stress and hence can be used as a biomarker for detecting oxidative stress.
Biomarkers associated with amyloid plaque formation
Methionine, homocysteine and S-adenosyl methionine are the products of cysteine metabolism. Methionine rich diets could result in the production of higher amounts of homocysteine in the plasma, contributing towards hyperhomocysteinemia, which is often correlated with dementia, due to cysteine-rich-Aβ plaque formation.
S-adenosyl methionine (SAM) serves as a ubiquitous methyl group donor and is necessary for the synthesis of neurotransmitters, neuronal membrane stability, and DNA methylation. A decreased level of SAM in urine could indicate an increased risk of AD where a similar case was reported in CSF samples Taurine has many diverse biological functions serving as a neurotransmitter in the brain and as a facilitator in the transport of ions, whose imbalance could facilitate amyloid plaque formation. It helps in maintaining the structural integrity of the neuronal membrane, which is downregulated in AD urine samples.
5-hydroxy indole acetic acid is a metabolite of serotonin, which is one of the important neurotransmitters in the brain, belonging to the tryptophan metabolism., Initially, tryptophan will get converted to serotonin by the action of two enzymes namely tryptophan hydrolase and aromatic L-amino acid decarboxylase and is then converted to 5-hydroxy indole acetic acid by monoamine oxidase, which was downregulated in the AD urine., Since serotonin is a neurotransmitter and is involved in the cognitive function of the brain, dysregulation of the above metabolite results in cognitive dysfunction.
Choline is an important metabolite since it is required for brain development, which serves as a precursor of acetylcholine and as a methyl donor in various metabolic processes., The levels of choline are decreased in urine samples of AD patients. 1-octen-3-ol, is upregulated in AD and is produced by the transformation of C18-polyunsaturated fatty acids mediated by lipoxygenase/hydroperoxide lyase. It is found that 1-octen-3-ol interferes in the dopamine packaging in cells and causes oxidation of dopamine into 3,4-dihydroxy phenylacetaldehyde. When this metabolite is upregulated, it results in the depletion of dopamine stored in the neurons resulting in cognitive decline.
3,4-dihydroxyphenyglycol is upregulated in AD urine and is produced from norepinephrine by the action of monoamine oxidase., Since norepinephrine is involved in the cognitive activities of the brain, its dysfunction could lead directly to a cognitive disorder. The relation between the mechanism involved in the Aβ plaque formation and 3,4-dihydroxyphenyglycol remains uncertain, despite several studies confirming the involvement of the metabolite in Aβ plaque formation.
Biomarkers associated with energy metabolism
Desaminotyrosine is upregulated in AD urine and is one of the phenolic acid metabolites of tyrosine by tyrosine aminotransferase,, which plays a role in neurotransmitter production and also has been proposed to be involved in Krebs cycle as a key intermediate in energy metabolism by undergoing iodination.
N-acryloyl glycine, a metabolite of fatty acids, is an acyl-glycine found in most human biofluids., Isobutyryl-L-carnitine is a product of the acyl-CoA dehydrogenases, which are a group of mitochondrial enzymes involved in fatty acid metabolism. Impaired energy metabolism, is well established in AD brains, indicating mitochondrial dysfunction., Therefore, the significant changes in these two metabolites seen in AD urine samples might indicate that AD is accompanied by, an underlying metabolic disorder affecting fatty acid oxidation and mitochondrial dysfunction. Their increased levels in urine can be used to diagnose AD associated with mitochondrial fatty acid β-oxidation.
1-(beta-D-ribofuranosyl)-1,4-dihydro-nicotinamide is a reduced form of nicotinamide riboside which is a precursor for NADH., NADH not only serves as an energy source but also helps in preventing Aβ plaque formation by activating peroxisome proliferator-activated receptor-γ coactivator-1α which helps in degrading beta-site amyloid precursor protein cleaving enzyme1 (BACE-1). Lower amounts of the aforementioned metabolite impaired energy metabolism along with accelerated Aβ plaque formation.
| Conclusion|| |
Three metabolites namely 5-hydroxy indole acetic acid, L-arginine and allantoin were found as putative urinary biomarkers since their alterations have been reported in both AD patients and AD mice. In AD, 5-hydroxy indole acetic acid level was downregulated and this indicates the reduced level of serotonin in the brain. The increased levels of L-arginine in AD urine implies enhanced levels of L-arginine in the brain which could be converted into nitric oxide due to the action of NO synthase leading to oxidative stress. Increase in the levels of allantoin could be due to the action of ROS on uric acid in the brain. Interestingly, these metabolites are also found to be elevated in the blood of MCI patients, which could have presumably arrived from brain through blood brain barrier. The predictive nature of these metabolites for AD diagnosis needs to be validated through longitudinal and cross-sectional studies.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
2019 Alzheimers disease facts and figures. Alzheimers & Dementia. 2019;15:321-87.
Seeman P, Seeman N. Alzheimers disease: β-amyloid plaque formation in human brain. Synapse 2011;65:1289-97.
Kritchevsky SB, Muldoon MF. Oxidative stress and aging: still a hypothesis. Journal of the American Geriatrics Society 1996;44:873-5.
Iqbal K, Liu F, Gong C-X, Grundke-Iqbal I. Tau in Alzheimer disease and related tauopathies. Current Alzheimer Research 2010;7:656-64.
Hawking ZL. Alzheimers disease: the role of mitochondrial dysfunction and potential new therapies. Bioscience Horizons: The International Journal of Student Research 2016;9.
Wang Y, Xu E, Musich PR, Lin F (2019). Mitochondrial dysfunction in neurodegenerative diseases and the potential countermeasure. CNS Neuroscience & Therapeutics. doi: 10.1111/cns.13116
Lancet T. The three stages of Alzheimers disease. The Lancet 2011;377:1465.
Zhang F, Wei J, Li X, Ma C, Gao Y. Early candidate urine biomarkers for detecting Alzheimer’s disease before beta amyloid plaque deposition in an APP (swe)/PSEN1dE9 transgenic mouse model 2018
Fukuhara K, Ohno A, Ota Y, Senoo Y, Maekawa K, Okuda H et al.
NMR-based metabolomics of urine in a mouse model of Alzheimer’s disease: identification of oxidative stress biomarkers. Journal of Clinical Biochemistry and Nutrition. 2013;52:133-8.
Peng J, Guo K, Xia J, Zhou J, Yang J, Westaway D et al.
Development of isotope labeling liquid chromatography mass spectrometry for mouse urine metabolomics: quantitative metabolomic study of transgenic mice related to Alzheimer’s disease. Journal of Proteome Research 2014;13:4457-69.
Cui Y, Liu X, Wang M, Liu L, Sun X, Ma L et al.
Lysophosphatidylcholine and amide as metabolites for detecting Alzheimer disease using ultrahigh-performance liquid chromatography–quadrupole time-of-flight mass spectrometry–based metabonomics. Journal of Neuropathology & Experimental Neurology 2014;73:954-63.
Kimball BA, Wilson DA, Wesson DW. Alterations of the volatile metabolome in mouse models of Alzheimer’s disease. Scientific Reports 2016;6:19495.
Yu J, Kong L, Zhang A, Han Y, Liu Z, Sun H et al.
High-throughput metabolomics for discovering potential metabolite biomarkers and metabolic mechanism from the APPswe/PS1dE9 transgenic model of Alzheimer’s disease. Journal of Proteome Research 2017;16:3219-28.
Zhang Y-Q, Tang Y-B, Dammer E, Liu J-R, Zhao Y-W, Zhu L et al.
Dysregulated urinary arginine metabolism in older adults with amnestic mild cognitive impairment. Frontiers in Aging Neuroscience 2019;11.
Risacher S, Saykin A. Neuroimaging biomarkers of neurodegenerative diseases and dementia. Seminars in Neurology 2013;33:386-416.
Toledo JB, Da X, Bhatt P, Wolk DA, Arnold SE, Shaw LM et al.
Relationship between plasma analytes and SPARE-AD defined brain atrophy patterns in ADNI. PLoS ONE 2013;8.
Bonda DJ, Mailankot M, Stone JG, Garrett MR, Staniszewska M, Castellani RJ et al.
Indoleamine 2, 3-dioxygenase and 3-hydroxykynurenine modifications are found in the neuropathology of Alzheimers disease. Redox Report 2010;15:161-8.
Takikawa O. Biochemical and medical aspects of the indoleamine 2,3-dioxygenase-initiated l-tryptophan metabolism. Biochemical and Biophysical Research Communications 2005;338:12-9.
Clarke G, Stone TW, Schwarcz R. The kynurenine pathway: towards metabolic equilibrium. Neuropharmacology 2017;112:235-6.
Ohashi H, Saito K, Fujii H, Wada H, Furuta N, Takemura M et al.
Changes in quinolinic acid production and its related enzymes following d-galactosamine and lipopolysaccharide-induced hepatic injury. Archives of Biochemistry and Biophysics 2004;428:154-9.
Guillemin GJ. Quinolinic acid, the inescapable neurotoxin. FEBS Journal 2012;279:1356-65.
Okuda S, Nishiyama N, Saito H, Katsuki H. Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine. Proceedings of the National Academy of Sciences 1996;93:12553-8.
Braconi D, Millucci L, Bernardini G, Santucci A. Oxidative stress and mechanisms of ochronosis in alkaptonuria. Free Radical Biology and Medicine 2015;88:70-80.
Amaya AA, Brzezinski KT, Farrington N, Moran GR. Kinetic analysis of human homogentisate 1,2-dioxygenase. Archives of Biochemistry and Biophysics 2004;421:135-42.
Ahn YJ, Park SJ, Woo H, Lee HE, Kim HJ, Kwon G et al.
Effects of allantoin on cognitive function and hippocampal neurogenesis. Food and Chemical Toxicology 2014;64:210-6.
Iris FF, Benzie W-yuen C, Tomlinson B. Simultaneous measurement of allantoin and urate in plasma: analytical evaluation and potential clinical application in oxidant: antioxidant balance studies. Clinical Chemistry 1999;45:901-4.
Tsahar E, Arad Z, Izhaki I, Guglielmo CG. The relationship between uric acid and its oxidative product allantoin: a potential indicator for the evaluation of oxidative stress in birds. Journal of Comparative Physiology B 2006;176:653-61.
Paik M-J., Lee S, Cho K-H, Kim K-R. Urinary polyamines and N-acetylated polyamines in four patients with Alzheimers disease as their N-ethoxycarbonyl-N-pentafluoropropionyl derivatives by gas chromatography-mass spectrometry in selected ion monitoring mode. Analytica Chimica Acta 2006;576:55-60.
Traina G, Bernardi R, Cataldo E, Macchi M, Durante M, Brunelli M. In the Rat brain acetyl-l-carnitine treatment modulates the expression of genes involved in neuronal ceroid lipofuscinosis. Molecular Neurobiology 2008;38:146-52.
Zhao B. Natural antioxidants in prevention and management of Alzheimer s disease. Frontiers in Bioscience 2012;E4:794-808.
Erez A, Nagamani SCS, Lee B. Argininosuccinate lyase deficiency-Argininosuccinic aciduria and beyond. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 2011;157:45-53.
Wu C-C., Singh P, Chen M-C., Zimmerli L. L-Glutamine inhibits beta-aminobutyric acid-induced stress resistance and priming in Arabidopsis. Journal of Experimental Botany 2009;61:995-1002.
Revett T, Baker G, Jhamandas J, Kar S. Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology. Journal of Psychiatry & Neuroscience 2013;38:6-23.
Sawada S, Yamamoto C. Gamma-D-glutamylglycine and cis-2,3-piperidine dicarboxylate as antagonists of excitatory amino acids in the hippocampus. Experimental Brain Research 1984;55.
Rothman S. Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death. The Journal of Neuroscience 1984;4:1884-91.
Hannibal L. Nitric oxide homeostasis in neurodegenerative diseases. Current Alzheimer Research 2016;13:135-49.
Mommersteeg PM, Schoemaker RG, Eisel UL, Garrelds IM, Schalkwijk CG, Kop WJ. Nitric oxide dysregulation in patients with heart failure. Psychosomatic Medicine 2015;77:292-302.
Jansen EE, Verhoeven NM, Jakobs C, Schulze A, Senephansiri H, Gupta M et al.
Increased guanidino species in murine and human succinate semialdehyde dehydrogenase (SSADH) deficiency. Biochimica et Biophysica Acta (BBA) − Molecular Basis of Disease 2006;1762:494-8.
Lee SH, Kim I, Chung BC. Increased urinary level of oxidized nucleosides in patients with mild-to-moderate Alzheimers disease. Clinical Biochemistry 2007;40:936-8.
Miller AL. The methionine-homocysteine cycle and its effects on cognitive diseases. Alternative medicine review: a journal of clinical therapeutic. U.S. National Library of Medicine 2003;8:7-19.
Linnebank M, Popp J, Smulders Y, Smith D, Semmler A, Farkas M et al.
S-adenosylmethionine is decreased in the cerebrospinal fluid of patients with alzheimer’s disease. Neurodegenerative Diseases 2010;7:373-8.
Wu J-Y., Prentice H. Role of taurine in the central nervous system. Journal of Biomedical Science 2010;17.
Joy T, Walsh G, Tokmakejian S, Uum SHV. Increase of urinary 5-Hydroxyindoleacetic acid excretion but not serum chromogranin a following over-the-counter 5-Hydroxytryptophan intake. Canadian Journal of Gastroenterology 2008;22:49-53.
Klein C, Roussel G, Brun S, Rusu C, Patte-Mensah C, Maitre M et al.
5-HIAA induces neprilysin to ameliorate pathophysiology and symptoms in a mouse model for Alzheimer’s disease. Acta Neuropathologica Communications 2018;6.
Bethea CL, Reddy AP, Christian FL. How studies of the serotonin system in macaque models of menopause relate to Alzheimer’s disease. Journal of Alzheimers Disease 2017;57:1001-15.
Bekdash RA. Choline and the brain: an epigenetic perspective. Advances in Neurobiology The Benefits of Natural Products for Neurodegenerative Diseases 2016 381-99.
Xue R, Dong L, Zhang S, Deng C, Liu T, Wang J et al.
Investigation of volatile biomarkers in liver cancer blood using solid-phase microextraction and gas chromatography/mass spectrometry. Rapid Communications in Mass Spectrometry 2008;22:1181-6.
Inamdar AA, Hossain MM, Bernstein AI, Miller GW, Richardson JR, Bennett JW. Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration. Proceedings of the National Academy of Sciences 2013;110:19561-6.
Martorana A, Koch G. Is dopamine involved in Alzheimers disease? Frontiers in Aging Neuroscience 2014;6.
Eisenhofer G, Aneman A, Hooper D, Holmes C, Goldstein DS, Friberg P. Production and metabolism of dopamine and norepinephrine in mesenteric organs and liver of swine. American Journal of Physiology-Gastrointestinal and Liver Physiology 1995;268.
Friedman JI, Adler DN, Davis KL. The role of norepinephrine in the pathophysiology of cognitive disorders: potential applications to the treatment of cognitive dysfunction in schizophrenia and Alzheimers disease. Biological Psychiatry 1999;46:1243-52.
Booth AN, Masri MS, Robbins DJ, Emerson OH, Jones FT, DeEds F. Urinary phenolic acid metabolites of tyrosine. Journal of Biological Chemistry 1960;235:2649-2.
Serruys P, Bourantas F, Muramatsu Diletti Onuma et al.
Bioresorbable scaffolds in the treatment of coronary artery disease. Medical Devices: Evidence and Research 2013;6:37-48.
Aliev G, Seyidova D, Neal ML, Shi J, Lamb BT, Siedlak SL et al.
Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-like pathology in aged transgenic mice. Annals of the New York Academy of Sciences 2002;977:45-64.
Aliev G, Smith MA, Obrenovich ME, Torre JCDL, Perry G. Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Alzheimer disease. Neurotoxicity Research 2003;5:491-504.
Chi Y, Sauve AA. Nicotinamide riboside, a trace nutrient in foods, is a Vitamin B3 with effects on energy metabolism and neuroprotection. Current Opinion in Clinical Nutrition and Metabolic Care 2013;16:657-61.
Gong B, Pan Y, Vempati P, Zhao W, Knable L, Ho L et al.
Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimers mouse models. Neurobiology of Aging 2013;34:1581-8.
[Figure 1], [Figure 2], [Figure 3]