Glutathione for cognitive function -
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Minimum Age: 55 Years. Maximum Age: 85 Years. Need Help? gov An official website of the U. Glutathione is a common physiological molecule with a number of essential roles. In humans, glutathione is used in many fundamental metabolic processes ranging from the nitric oxide cycle to dietary mineral incorporation.
During cellular differentiation, glutathione triggers stem cells to change their characteristics and transform into the kind of cell the body needs.
Cells then migrate to the location where they will reside in the body and complete the final touches necessary for maturation.
To scavenge circulating ROS, glutathione binds ROS to itself, becoming oxidized. Research has linked glutathione to a number of non-ROS detoxification processes, immune cell function, and the regulation of induced cell death. Glutathione is a good candidate for promoting cognitive function due to the relationship between cognitive function and oxidative stress.
However, one of the primary molecular mechanisms that is detrimental to cognitive function is oxidative stress. Oxidative stress activates many other detrimental mechanisms associated with cognitive function, including inflammation and cell death signals, while interfering with the functioning of many cellular and molecular processes.
As with many pathologies associated with aging, oxidative stress slowly builds as a result of the aging process, exposure to chemical stressors, parasympathetic nervous system activation, and unrepaired stress damage.
Antioxidants and molecules that help the brain cope with oxidative stress, like glutathione, are therefore excellent candidates for helping to maintain cognitive function.
Such built-up damage is one of the major causes of age-related cognitive deficits. As the brain ages, neurons are less capable of forming or strengthening connections to one another and learning becomes more difficult.
Simultaneously, neuronal death and degeneration accelerate with age, eventually impairing cognition. Depending on the location of neuronal death, different symptoms of loss of cognitive ability can occur; the most notable symptoms of cognitive impairment, like difficulty with memory recall, are a result of loss of neurons within the temporal lobes.
Glutathione has been identified as having an important role to play in helping to maintain normal cognitive function owing to its ability to help the body cope with oxidative stress.
The study did not examine whether the glutathione molecules had scavenged reactive oxygen species at the time of measurement, necessitating further research. A study found that increased ratios of oxidized glutathione to its unoxidized state in the anterior and cingulate cortices of the brain were associated with symptoms of mild losses of cognitive function.
This means both the location and oxidation state of high glutathione concentrations are critical diagnostically. High concentrations of oxidized glutathione in the brain are evidence that the brain can be in a compromised state, whereas high concentrations in the blood plasma are healthy and normal.
This is because oxidized glutathione must return to the bloodstream from the brain to discharge the ROS it carries into a metabolic process that can make use of them constructively. As such, high concentrations of oxidized glutathione in the brain can mean that there is not enough glutathione to remove all of the reactive oxygen species that are circulating, indicating significant levels of stress.
The neuropsychological battery of tests at various time points for cognitive profile evaluation should be part of the upcoming clinical study.
Finally, the GSH level in the hippocampus region and its correlation with the cognitive score will be a great measure for the identification of the impact of GSH supplementation both for MCI and AD compared to participants treated with placebo.
Thanks to Ms. Divya Dwivedi, Project Assistant in the NINS lab NBRC , for participating in literature search and Mr. Ritwick Mishra Clinical Coordinator at NINS lab for proof reading. N Engl J Med , 56— Eur Arch Psychiatry Clin Neurosci , 14— Nat Rev Neurosci 10 Suppl: , S34—S Science , — Med Clin North Am , — Free Radic Biol Med , — Casetta I , Govoni V , Granieri E Oxidative stress, antioxidants and neurodegenerative diseases.
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Neurology , — Dringen R , Hirrlinger J Glutathione pathways in the brain. Biol Chem , — Stryer L Glutathione serves as a sulfhydryl buffer and amino acid transporter. In Biochemistry, W. Freeman, New York, pp. Brain Res , 60— J Neurosci Res , — J Parkinson Dis 7: , — Shukla D , Mandal PK , Ersland L , Renate Gruner E , Tripathi M , Raghunathan P , Sharma A , Chaithya GR , Punjabi K , Splaine C A multi-center human brain glutathione conformation study from magnetic resonance spectroscopy.
J Alzheimers Dis , — Liu H , Wang H , Shenvi S , Hagen TM , Liu RM Glutathione metabolism during aging and in Alzheimer disease. Slivka A , Spina MB , Cohen G Reduced and oxidized glutathione in human and monkey brain. Neurosci Lett , — Free Radic Res , — Neurobiol Aging , — Ansari MA , Scheff SW Oxidative stress in the progression of Alzheimer disease in the frontal cortex.
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Magn Reson Med , — Terpstra M , Henry PG , Gruetter R Measurement of reduced glutathione GSH in human brain using LC model analysis of difference-edited spectra. Magn Reson Med , 19— Duffy SL , Lagopoulos J , Hickie IB , Diamond K , Graeber MB , Lewis SJ , Naismith SL Glutathione relates to neuropsychological functioning in mild cognitive impairment.
Alzheimers Dement , 67— Kovacs-Nolan J , Rupa P , Matsui T , Tanaka M , Konishi T , Sauchi Y , Sato K , Ono S , Mine Y In vitro and ex vivo uptake of glutathione GSH across the intestinal epithelium and fate of oral GSH after in vivo supplementation. J Agric Food Chem , — Honda Y , Kessoku T , Sumida Y , Kobayashi T , Kato T , Ogawa Y , Tomeno W , Imajo K , Fujita K , Yoneda M , Kataoka K , Taguri M , Yamanaka T , Seko Y , Tanaka S , Saito S , Ono M , Oeda S , Eguchi Y , Aoi W , Sato K , Itoh Y , Nakajima A Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: An open-label, single-arm, multicenter, pilot study.
BMC Gastroenterol , Allen J , Bradley RD Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers.
HEIDI Glutqthione Mood-enhancing Fat Burner. The reality behind nutrition myths unsw. Findings of the study were recently published in the Neurochemistry International Functon. The Glutathione for cognitive function also found significant Glutathipne improvements in funtcion mice as determined using the Morris water maze, a test often used to test memory in mice. Supplementation with γ-GC can transiently augment cellular glutathione levels by bypassing the regulation of glutathione homeostasis. Associate Professor Wallace Bridge first became interested in the therapeutic potential of γ-GC in com brand of dietary supplements.Metrics cognitife. Increasing evidence implicates oxidative stress OS Guarana and sports performance Alzheimer disease AD and mild cognitive impairment MCI.
Depletion of the brain Natural stamina enhancers glutathione Ror may Glutahione important cognitivr OS-mediated neurodegeneration, though studies Glutatione post-mortem brain GSH changes in AD Glutatuione been inconclusive. Recent Glurathione vivo measurements Improve mental energy and focus the brain and Hydration for staying refreshed GSH may shed light on GSH changes earlier in the Mood-enhancing Fat Burner. To quantitatively review in vivo Funcction in AD and MCI compared to healthy covnitive HC Glutthione meta-analyses.
Studies with Metabolic health research vivo brain or blood GSH levels in Glugathione or AD with a HC group were identified fir MEDLINE, PsychInfo, and Embase —June Outcome measures included brain GSH Functikn Point Glutatgione Spectroscopy MEGA-PRESS versus non-MEGA-PRESS and blood GSH intracellular versus extracellular dunction AD and MCI.
Blood ofr GSH decrease is seen in MCI, while functiion intra- and extracellular decreases functoon seen in AD. Brain GSH is decreased fo AD and MCI in Muscle growth supplements for skinny guys analysis.
Potential bias and heterogeneity suggest the need for measurement standardization and additional fumction to explore sources of heterogeneity.
In AD, the brain shows hallmark features of amyloid beta Aβ plaque accumulation Glutathionf neurofibrillary tangles Glutathoine by hyperphosphorylated tau protein [ 2 ], although prior to diagnosis, a series of neuropathological changes and cognitive decline occur fro 3 ].
Currently, Glutathione for cognitive function are no approved pharmacological Sports nutrition for recovery for MCI, Goutathione MCI is recognized to provide a window of opportunity coggnitive address modifiable risk factors and potentially prevent further progression to dementia [ 6 ].
For AD, approved interventions such as flr inhibitors and NMDA antagonists have modest cognirive on cognitive decline but are not able to Sports nutrition resources the course of disease fpr 7 ].
Development Glutathlone interventions targeting amyloid beta plaques and tau protein Glutayhione also have not Glutathioone successful [ 89 ], and the number of phase 3 trials focused on amyloid intervention has decreased fuhction [ 10 ].
Overall, this cognitige the need to identify additional mechanisms functtion may Glutathoone to progression of Cogbitive. Increasing evidence implicates oxidative stress OS with age-related neurodegeneration, neurotoxicity, and neuronal loss [ 12 ].
The brain is particularly susceptible to OS due to high fjnction required to maintain synaptic Glhtathione, and increased OS is funnction with AD Glutathione for cognitive function MCI.
Gluhathione suggests antioxidant depletion and altered endogenous antioxidant ffor precedes OS [ functuon13 ]. Glutathione GSH is the primary funvtion defense molecule in the brain [ 12 Gultathione. It is a Glutathionne of glutamate, cysteine, and glycine and functlon antioxidant effects dor donating a reducing equivalent to a cognitice oxygen species to neutralize it [ Glutathiobe ].
This reaction can occur both non-enzymatically and Gluyathione catalysis by glutathione peroxidase [ 14 dor, 15 ]. Cognittive previous meta-analysis of GSH levels in cognitibe AD brain tissue found cogntive evidence of significant change in Glutathioe in AD cogniitve to controls across several brain regions [ cognituve ].
The authors also noted that little quantitative post-mortem data were available for Gluutathione. However, the quality of post-mortem Raspberry ketones for natural detoxification can be variable, as GSH concentration in the brain drops rapidly after death and is affected Glutahhione many pre- and post-mortem factors [ 1920 ].
Glutatione studies have measured in vivo GSH in the brain using magnetic resonance spectroscopy MRS and peripherally in the blood [ 2122Glutathione for cognitive function ].
These in vivo measures Glutzthione arguably more accurate and provide additional information to help determine Gltuathione GSH functoin be considered a clgnitive target. Therefore, the focus of the fubction work is to review quantitatively the Gluyathione vivo GSH changes in the brain and the periphery Glhtathione AD and MCI compared to Satisfying your thirst, one sip at a time, using cognitjve methods.
The Glutathioe outlined by the PRISMA guidelines was used for G,utathione review [ 24 ]. A sample Glutathiond strategy of brain GSH for Embase is detailed in Cognitiive 1.
Two of the 3 independent reviewers JC, MT, and JS assessed each retrieved reference. Screening was done by reviewing reference abstracts to exclude case reports, research in Gluyathione, conference abstracts, dissertations, Glutathuone, and scientific meeting reports. Full-text articles were then assessed.
Study inclusion cognitivee were 1 original clinical studies reporting in vivo GSH levels in Mood-enhancing Fat Burner brain, serum, plasma, Glutathoone blood cells 2 ; Glutahione diagnosis Glutathione for cognitive function MCI or AD using standardized diagnosis; and 3 inclusion of cor Mood-enhancing Fat Burner healthy and cognitively intact Increase muscle definition group.
Cognigive measuring post-mortem GSH concentrations without any funciton of in vivo Glutathionf were excluded. At least cobnitive reviewers Glutatjione each article for funcfion eligibility independently, results were Glutathilne and disagreements Mood-enhancing Fat Burner inclusion were reached by consensus.
Mean ±SD GSH concentrations for MCI, AD, and control groups were extracted from each article. Study and participant characteristics fot collected Plant-based nutrition for endurance athletes a standardized form.
Population Nutritious meal options mean age, sex proportion, years of education, cognitive test scores and study variables inclusion cognihive, diagnosis method, Gluutathione measurement methodology were also extracted where Gluhathione.
Corresponding authors of publications were contacted for missing data. When studies reported multiple brain regions or several blood components plasma, serum, blood cellseach region or component was extracted as a sub-study. StataIC 16 was used for the main and subgroup analyses.
As funvtion used different scales of measurement, SMDs were chosen to summarize between group differences since it can better adjust for the different scaling used [ 26 ]. Random effects models are preferable when significant heterogeneity is expected because they account for variable underlying effects in estimates of uncertainty, including both within-study and between-study variances [ 27 ].
In brain GSH measurements, different acquisition methodologies, internal references, and brain regions have been used. In blood GSH, different assays and blood components were also used. These factors were expected to contribute to significant heterogeneity. The Q statistic was calculated using a chi-square analysis to assess heterogeneity among combined results.
A significant Q statistic indicates diversity in the characteristics of the combined results. Inconsistency was calculated using an I 2 statistic to determine the impact of heterogeneity. Potential heterogeneity was explored with inverse-variance weighted meta-regression analyses and subgroup analysis.
Meta-regression cogntiive the standard mean differences against mean age, sex proportion, or mean Mini-Mental State Examination MMSE scores if at least 10 independent studies were included based on Cochrane recommendations.
Subgroups were determined a priori to determine if MRS acquisition protocol, internal reference, or brain regions contributed to heterogeneity in brain GSH measurements.
The search returned unique records Fig. Of the records screened, 46 studies were Gluttahione as Glutatbione were non-clinical studies including reviews, editorials, and or conference abstractsstudies were excluded because those studies involved non-human subjects, 28 studies were excluded as they were not conducted in AD or MCI patients, 1 study was excluded as it did not have a healthy control group, and 14 studies were excluded as they did not measure GSH in the brain.
One paper was excluded as it was an erratum clarification that was not relevant to the results. One additional study was excluded from quantitative analysis as full results could not be obtained.
A total of 4 studies functoon included in the AD brain GSH meta-analysis [ 29303132 ], and 4 studies were included in the MCI analysis [ 30333435 ] Table 2. Studies reporting multiple brain locations were analyzed as sub-studies, and when bilateral measures were available, the left and right voxels were averaged.
A total of 7 studies and sub-studies were included for AD brain GSH analysis and 8 studies and sub-studies were included for MCI analysis. Assessment of included studies showed a consistently low risk of bias in the brain GSH literature Table 3. Of the records screened, 40 studies were excluded as they were non-clinical studies including reviews, editorials, and or conference abstracts ; 70 studies were excluded because these studies involved non-human subjects; 81 studies were excluded as they were not conducted in AD or MCI patients; 23 studies were excluded as they were post-mortem studies; 9 studies were excluded as they did not include a healthy control group; 47 studies were excluded as they did not measure GSH in whole blood, plasma, or serum; and 2 were excluded as full results could not be obtained.
A total of 27 studies qualified, with 26 of these studies being included in the AD blood GSH meta-analysis [ 3637383940414243444546474849505152535455565758596061 ], and 7 of these studies being included in the MCI analysis [ 39 cognitkve, 404243465262 ].
The risk of bias was variable in the AD blood GSH literature but consistently low in MCI blood GSH literature Table 3.
For MCI patient samples, the Petersen criteria [ 70 ] were commonly used to diagnose MCI, though other studies used revised Petersen criteria [ 71 ], or a combination of the Montreal Cognitive Assessment, DSM-IV, Clinical Dementia Rating, and Mini-Mental State Examination [ 3462 ].
While amnestic-type MCI patients were specifically selected in 2 blood GSH studies [ 4243 ], most of the studies measuring blood GSH and all the studies measuring brain GSH either did not specify or included both amnestic and non-amnestic patients Table 2.
Subgroup analyses of different brain regions and use of creatine or water as the reference molecule did not significantly reduce heterogeneity in brain GSH measurements data not shownwith the exception of the study by Marjanska et al.
Forest plot displaying brain GSH concentrations in AD and control subjects, with the subgroup of studies using the MEGA-PRESS protocol at the bottom. Negative values denote lower GSH in AD subjects while positive values denote higher in GSH in AD compared to controls.
ROI indicates the region of interest: PMC posteromedial cortex, PCC posterior cingulate cortex, OCC occipital cortex, HP hippocampus, FC frontal cortex, ACC anterior cingulate cortex.
Forest plot displaying brain GSH concentrations in MCI and control subjects, with the subgroup of studies using the MEGA-PRESS protocol at the bottom. Negative values denote lower GSH in MCI subjects while positive values denote higher in GSH in MCI compared to controls.
ROI indicates the region of interest: ACC anterior cingulate cortex, PCC posterior cingulate cortex, FC frontal cortex, HP hippocampus. Subgroup analysis of GSH assay type did not significantly reduce heterogeneity in blood GSH measurements. Meta-regressions with the mean age and MMSE scores did not significantly reduce heterogeneity data not shown.
Forest plot displaying blood GSH concentrations in AD and control subjects, by the intracellular and extracellular GSH subgroups. Positive values denote higher in GSH in AD while negative values denote higher GSH in control subjects.
ROI region of interest. Forest plot displaying blood GSH concentrations in MCI and control subjects by the intracellular and extracellular GSH subgroups. Positive values denote higher in GSH in MCI while negative values denote higher GSH in control subjects.
Meta-regression demonstrating inverse correlation between the proportion of male study participants and the standardized mean difference SMD of blood GSH level between AD participants and healthy controls. The size of the circles is proportional to study weights.
This meta-analysis did not find significant differences between MCI and controls, nor AD vs. controls in in vivo brain GSH overall; however, subgroup analysis suggests that brain GSH may be decreased in AD and MCI in studies using MEGA-PRESS to acquire GSH covnitive.
GSH is an essential antioxidant in brain cells that detoxifies reactive oxygen species, and in vitro studies have linked GSH homeostasis disruption to oxidative stress in neurological diseases [ 1472 ]. Increased lipid peroxidation and oxidative stress have been described in AD and MCI [ 737475 ]; however, brain GSH has not been as well-characterized.
The results of this in vivo brain GSH study mirrors a previous meta-analysis examining post-mortem GSH levels in brain tissue, where they reported that in post-mortem AD brain samples, GSH appeared to be unchanged across several brain regions [ 18 ].
It should be noted that GSH data obtained from post-mortem brain samples are variable in quality, as brain GSH is affected by many pre- and post-mortem factors and changes quickly after death [ 1920 ].
Interestingly, the subgroup analysis of brain GSH suggested that studies using MEGA-PRESS to acquire brain GSH measurements reported lower brain GSH in both AD and MCI patients compared to controls.
The existing MRS studies measuring in vivo brain GSH in AD and MCI used several protocols, including STEAM [ 3234 ], PRESS [ 33 ], MEGA-PRESS [ 3035 ], and J-PRESS [ 31 ].
The high heterogeneity and significant risk of bias seen in these in vivo brain GSH studies suggests the need to standardize in vivo GSH measurement methodology. And while qualitative assessment of brain GSH studies is relatively consistent, there may be other factors contributing to heterogeneity.
MEGA-PRESS may be a promising protocol, although the current MEGA-PRESS studies reporting brain GSH in MCI and AD were from a single research group, which may have artificially reduced heterogeneity.
Currently, in vivo brain markers in AD and MCI mainly include positron emission tomography scanning of amyloid, tau, and glucose metabolism, as well as brain structural imaging using MRI such as hippocampal atrophy [ 81 ].
However, it is now recognized that development and progression of AD is likely due to multiple etiologies, and there is increasing evidence implicating oxidative stress OS as an early event in the trajectory of MCI and AD [ 21875 ].
Thus, examining in vivo brain GSH as a biomarker would complement the current arsenal of brain biomarkers and may aid in identifying and characterizing changes in the early stage of cognitive impairment or those who are at risk. This meta-analysis found that in AD, there was a significant decrease in blood GSH compared to controls, but no difference between MCI and controls.
Blood GSH measurements came from extracellular sources in serum and plasma, or intracellular sources in erythrocytes, whole blood both erythrocytes and leukocytesor leukocytes.
In serum and plasma, reduced GSH is ufnction released by hepatocytes for uptake by the kidney, lung, intestine, and other organs [ 14 ].
Therefore, in the periphery, extracellular GSH reflects the antioxidant capacity of the liver, and the liver, due to its function in metabolizing xenobiotics and endogenous molecules, has high antioxidant capacity [ 16 ].
: Glutathione for cognitive function| Categories | Ffunction CDR, Mood-enhancing Fat Burner, and Fog signify enhanced cognitive impairment. Gauthier S, Reisberg B, Zaudig M, Petersen Glutathione for cognitive function, Ritchie K, Broich K, Metabolism boosters al. Determination of malondialdehyde, reduced glutathione levels and APOE4 allele frequency in late-onset Alzheimer's disease in Denizli. After all, consuming more antioxidant-rich foods is one of the easier lifestyle choices we can make to manage this condition. N Engl J Med — |
| Glutathione for Alzheimer's Disease | N-Acetylcysteine, a glutamate modulator, in the treatment of trichotillomania. Archives of General Psychiatry 66 , — Halliwell B Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs and Aging 18 , — Halliwell B Gutteridge JR Free Radicals in Biology and Medicine , 3rd edn. Oxford : Clarendon. Google Preview. Herken H Uz E Ozyurt H Sogut S et al. Evidence that the activities of erythrocyte free radical scavenging enzymes and the products of lipid peroxidation are increased in different forms of schizophrenia. Molecular Psychiatry 6 , 66 — Knable MB Barci BM Webster MJ Meador-Woodruff J et al. Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium. Molecular Psychiatry 9 , — Kodydkova J Vavrova L Zeman M Jirak R et al. Antioxidant enzymes and increased oxidative stress in depressive women. Clinical Biochemistry 42 , — Lavoie S Chen Y Dalton TP Gysin R et al. Curcumin, quercetin, and tBHQ modulate glutathione levels in astrocytes and neurons: importance of the glutamate cysteine ligase modifier subunit. Journal of Neurochemistry , — Lucca G Comim CM Valvassori SS Gislaine ZR et al. Effects of chronic mild stress on the oxidative parameters in the rat brain. Neurochemistry International 54 , — Increased oxidative stress in submitochondrial particles into the brain of rats submitted to the chronic mild stress paradigm. Journal of Psychiatric Research 43 , — Meister A Transport and metabolism of glutathione and gamma-glutamyl amino acids. Biochemical Society Transactions 11 , — Glutathione metabolism and its selective modification. Journal of Biological Chemistry , — Ng F Berk M Dean O Bush AI Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. International Journal of Neuropsychopharmacology 11 , — Ozcan ME Gulec M Ozerol E Polat R et al. Antioxidant enzyme activities and oxidative stress in affective disorders. International Clinical Psychopharmacology 19 , 89 — Prabakaran S Swatton JE Ryan MM Huffaker SJ et al. Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Sarandol A Sarandol E Eker SS Erdinc S et al. Major depressive disorder is accompanied with oxidative stress: short-term antidepressant treatment does not alter oxidative—antioxidative systems. Human Psychopharmacology 22 , 67 — Sun X Wang JF Tseng M Young LT Down regulation in components of mitochondrial electron transport chain in post-mortem frontal cortex from subjects with bipolar disorder. Journal of Psychiatry Research 31 , — Tian SY Wang JF Bezchlibnyk YB Young LT Immunoreactivity of 43 kDa growth-associated protein is decreased in post mortem hippocampus of bipolar disorder and schizophrenia. Neuroscience Letters , — Torrey EF Webster M Knable M Johnston N et al. Stanley Foundation Brain Collection and Neuropathology Consortium. Schizophrenia Research 44 , — Tosic M Ott J Barral S Bovet P et al. Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene. American Journal of Human Genetics 79 , — Wang JF Shao L Sun X Young LT Increased oxidative stress in the anterior cingulate cortex of subjects with bipolar disorder and schizophrenia. Bipolar Disorders 11 , — Yanik M Erel O Kati M The relationship between potency of oxidative stress and severity of depression. Acta Neuropsychiatrica 16 , — Yao JK Leonard S Reddy R Altered glutathione redox state in schizophrenia. Disease Markers 22 , 83 — Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Navbar Search Filter International Journal of Neuropsychopharmacology This issue Neuroscience Books Journals Oxford Academic Mobile Enter search term Search. Issues Volume 27, Issue 2, February In Progress Volume 27, Issue 1, January Browse all Advance articles Submit Author Guidelines Submission Site Open Access Why publish with IJNP? Alerts About About IJNP About the CINP Editorial Board Advertising and Corporate Services Journals Career Network Self-Archiving Policy Contact Us Journals on Oxford Academic Books on Oxford Academic. Alerts About About IJNP About the CINP Editorial Board Advertising and Corporate Services Journals Career Network Self-Archiving Policy Contact Us Close Navbar Search Filter International Journal of Neuropsychopharmacology This issue Neuroscience Books Journals Oxford Academic Enter search term Search. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Statement of Interest. Journal Article. Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Gawryluk , Jeremy W. Department of Psychiatry, University of British Columbia. Oxford Academic. Jun-Feng Wang. Ana C. Li Shao. Trevor Young. Address for correspondence: Dr L. Young, Department of Psychiatry, University of British Columbia. Revision received:. PDF Split View Views. Cite Cite Jeremy W. Select Format Select format. ris Mendeley, Papers, Zotero. enw EndNote. bibtex BibTex. txt Medlars, RefWorks Download citation. Permissions Icon Permissions. Close Navbar Search Filter International Journal of Neuropsychopharmacology This issue Neuroscience Books Journals Oxford Academic Enter search term Search. Abstract Accruing data suggest that oxidative stress may be a factor underlying the pathophysiology of bipolar disorder BD , major depressive disorder MDD , and schizophrenia SCZ. Bipolar disorder , depression , glutathione , oxidative stress , schizophrenia. Open in new tab Download slide. Table 1 Demographic data for post-mortem brain tissue. Open in new tab. Google Scholar PubMed. OpenURL Placeholder Text. Google Scholar Crossref. gov A. gov website belongs to an official government organization in the United States. gov website. Share sensitive information only on official, secure websites. Start: February 15, End: May Enrollment: Research suggests that low levels of glutathione, a protective substance made in the body, may be linked to Alzheimer's disease. Glutathione levels can be increased by taking supplements of glycine and cysteine, which combine in the body to make glutathione. This clinical trial will evaluate the effects of glycine-cysteine supplements in people with Alzheimer's disease. Participants will be randomly assigned to receive supplements of either glycine-cysteine or a placebo for 24 weeks. Human clinical trials have reported clinically relevant benefits of supplementing with glutathione or N-acetyl cysteine a glutathione precursor to replenish brain antioxidant defense homeostasis , specifically liposomal glutathione. Glutathione is a vital antioxidant in the body that modulates the redox balance and oxidative stress. Therefore, glutathione may play an important role in healthy aging and overall brain health. By Danielle Moyer, MS, CNS, LDN. Designs for Health has been dedicated to being the most trusted source for superior quality, science-based nutritional products for nearly three decades. The blogs we publish here cover a range of topics, including new and original approaches to diet and healthcare, analyses of the latest cutting-edge research, deep-dives into specific nutrients, botanicals, nutraceuticals and more, all fully referenced for those who want to dig deeper into the primary literature. Glutathione for Brain Health and Healthy Aging. 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| Bioavailability. Efficacy. Outcome | Journal of Neuroinflammation volume 15 , Article number: 17 Cite this article. Metrics details. Redox signaling, which can be assessed by circulating aminothiols, reflects oxidative stress OS status and has been linked to clinical cardiovascular disease and its risk factors. These, in turn, are related to executive function decline. OS may precede the pro-inflammatory state seen in vascular disease. The objective of this study is to investigate the association between aminothiol markers of OS and inflammation in cognitive decline, especially in the executive cognitive domain which is highly susceptible to cardiovascular risk factors and is an important predictor of cognitive disability. These participants were followed for four consecutive years with a yearly cognitive assessment conducted using computerized versions of 15 cognitive tests. Peripheral cystine, glutathione, their disulfide derivatives, and C-reactive protein CRP were measured. None of the other OS markers or CRP were linked to cognitive decline over 4 years. Increased OS reflected by decreased glutathione was associated with a decline in executive function in a healthy population. In contrast, inflammation was not linked to cognitive decline. OS may be an earlier biomarker that precedes the inflammatory phase of executive decline with aging. Oxidative stress OS that is marked by the increased production of reactive oxygen species ROS has been implicated in both cardiovascular pathophysiology and in neurodegeneration [ 1 , 2 , 3 ]. However, clinical trials with non-specific antioxidants such as vitamins have failed to demonstrate benefit. This may be related to the fact that a focus on ROS is simplistic, as some ROS species such as superoxide anion radical, hydrogen peroxide, and nitric oxide also play an essential role in signaling and other physiological processes in the vascular system and the brain [ 5 ]. An alternative approach of OS as a disruption of redox signaling and control has been proposed [ 6 ]. Aminothiol-containing proteins are prone to oxidation-reduction reactions. Biological organization and several physiological functions are mediated by these switches in proteins [ 7 ]. In this organizational structure, glutathione functions as a major antioxidant in tissues, supporting the elimination of peroxides and detoxification of reactive aldehydes and other toxic chemicals. In the plasma, cysteine undergoes oxidation to its disulfide, cystine, which must be cleared from the circulation and reduced back to cysteine to prevent disruption of the thiol switching mechanisms [ 8 ]. Quantifying these circulating thiol proteins thus may provide a more accurate assessment of systemic OS allowing the investigation of its contribution to aging and chronic disease [ 9 ]. We have shown that increased OS as assessed by measuring circulating aminothiols is associated with cardiovascular risk factors, subclinical cardiovascular disease, and are strong predictors of incident adverse cardiovascular events and mortality [ 10 , 11 , 12 , 13 , 14 ]. Since cardiovascular risk factors are also associated with a decline in executive function, we hypothesized that aminothiol markers of OS will be predictive of cognitive decline in healthy adults without dementia [ 15 , 16 ]. To test our hypothesis, we investigated the association between aminothiol markers of OS as well as the inflammatory marker, C-reactive protein CRP , and cognitive decline, especially in the executive cognitive domain which is highly susceptible to cardiovascular risk factors in a healthy population free of significant cardiovascular disease or cognitive disorders. edu as described previously [ 18 ]. The Emory University Institutional Review Board approved the protocols, and informed consent was obtained from all participants. Exclusion criteria were a history in the past year of hospitalization except for accidents ; severe psychosocial disorders; addition of new prescription medications to treat a chronic disease except for changes in antihypertensive or antidiabetic agents ; drug abuse or alcoholism; a current active malignant neoplasm; uncontrolled or poorly controlled autoimmune, cardiovascular, endocrine, gastrointestinal, hematologic, infectious, inflammatory, musculoskeletal, neurological, psychiatric, or respiratory disease; and any acute illness in the 2 weeks before the baseline studies. Physical measures blood pressure, heart rate, dual-energy X-ray absorptiometry, body mass index, and treadmill testing , laboratory tests metabolic, hematologic and inflammatory markers , cardiovascular function, health behaviors, medication profiles, mental health markers, and cognitive function were measured at yearly intervals. Commonly employed versions of neuropsychological measures were administered via computer at baseline and then yearly for a total of four times, using a software developed by Aharonson and colleagues [ 19 , 20 , 21 ]. Other tests, such as executive function, included identifying the odd pattern by pressing the corresponding number of the pattern out of multiple patterns. The digit symbol substitution test included showing the subject a code for symbols and digits then the subject is instructed to substitute each symbol with the appropriate digit underneath it. Digit span instructs the subject to repeat a set of digits forward or backward after showing them the set of digits. A full description of this battery is available here [ 19 , 20 , 21 ]. Cognitive scores for cognitive domains were derived using principal component analysis with Varimax orthogonal rotation and Kaiser normalization to perform the exploratory factor analysis and was then followed with a confirmatory factor analysis by exploring the correlations and model fit of the derived factor-saved scores as reported previously in our reports [ 22 , 23 ]. The factor analysis resulted in deriving three scores related to executive function, memory, and working memory. The distributions of the cognitive scores were extremely skewed to the right, as were the raw scores, suggesting a high-performance level of the participants probably related to the high educational levels of the sample: Factor analysis and cut-off were derived from the baseline sample of participants. Plasma cysteine CyS , its oxidized form cystine CySS , glutathione, and its oxidized form glutathione disulfide GSSG were measured by high-performance liquid chromatography [ 6 , 9 ]. Sample collection and storage conditions have been previously described [ 24 ]. Analyses by high-performance liquid chromatography were performed after dansyl derivatization on a 3-aminopropyl column with fluorescence detection. Metabolites were identified by coelution with standards and quantified by integration relative to the internal standard, with validation relative to external standards. Higher levels of the oxidized derivatives and lower levels of the reduced forms represent increased OS. The coefficient of variation for cystine is 3. To estimate the age, gender, and race-adjusted change in the calculated cognitive scores, we performed multiple regression analysis after adjusting for these three demographic variables. Baseline correlations between OS markers and cognitive scores were performed using regression analyses. Cognitive scores and aminothiol levels were included as discrete variables due to their skewness in the longitudinal analysis. We used binomial regression with generalized estimating equations GEE for repeated discrete measures. GEE is appropriate for binary repeated correlated measures, and it allows for the estimation of risk in the population [ 25 , 26 ]. The cumulative relative risk of having cognitive decline below the cut-off derived from the baseline score was calculated during the follow-up [ 27 ]. To assess the relation between changes in OS and cognition, we first calculated a within-subject slope for each measure yearly change and then performed multiple standardized regressions between the rate of change in OS markers and cognitive measures. All analysis models were adjusted for age, gender, race, education, systolic blood pressure, statin, and antihypertensive therapy. All analyses were conducted in SAS V9. The median number of follow-up visits with OS and cognitive assessments was 4, and the mean follow-up time was Over the study period, the age-, gender-, race-adjusted decline in the executive domain was 0. None of the other markers were associated with baseline memory domains Table 2. Baseline CRP, CYS, CYSS, and GSSG levels were not associated with the change in executive function or other memory domains. Association of baseline glutathione with the proportion of subjects with decreased executive function over the 4-year period. For every unit decline in glutathione, executive function declined by 1. This study demonstrates that decreased circulating levels of glutathione predict the age-related decline in the executive domain, an area of cognition that is particularly susceptible to cardiovascular disease. In addition, higher levels of the oxidized glutathione, GSSH, are related to lower performance on both memory and working memory but better executive function. Most uniquely in our analysis, we demonstrate that age or time -related changes in OS correlate with the age-related decline in the executive domain. Extending our previous reports relating aminothiol levels with subclinical vascular disease and incident cardiovascular events, we now demonstrate that circulating aminothiol levels serve as a biomarker of change in executive function [ 11 ]. The existence of a role for OS in vascular disease and cognitive aging has been suggested, but most studies have so far focused on ROS [ 28 ]. Our findings indicate that glutathione may predict aging-related decline in executive function. This is important because decline in executive function is a better predictor, more so than memory, of future functional loss in normal controls and those with mild cognitive impairment or dementia. Use of free radical-scavenging antioxidants such as vitamin E has failed to show a consistent benefit on cognitive preservation and has been linked to increased cardiovascular mortality [ 29 , 30 ]. However, vitamin E supplementation can lower glutathione levels through its effect on the glutathione S-transferase and may potentially exacerbate OS [ 31 ]. Our results demonstrating the link between aminothiol markers and cognitive preservation may offer an explanation for the inconsistent findings with vitamin E supplementation trials on cognitive outcomes. The underlying mechanisms remain unknown, although increased OS is thought to be an initial trigger [ 33 ]. Glutathione plays a key role in the antioxidant defense of neuronal cells, and circulating glutathione levels are reduced in AD [ 34 ]. Our findings show that the plasma glutathione levels predict future decline in cognition. Moreover, individuals who experience decreases in glutathione level over time also have a greater decline in their cognition. These findings potentially offer new targets for the prevention and treatment of cognitive loss with aging, especially that related to executive function where no therapy is currently available. In the brain, glutathione synthesis varies by cell type and depends on its ability to use available extracellular glutathione precursors. Neurons rely on the presence of extracellular cysteine as a precursor for glutathione [ 35 ]. Glutathione is also released from astrocytes [ 36 , 37 , 38 , 39 , 40 ] and can be imported from blood into the brain through the blood-brain barrier [ 41 , 42 ] In particular, a sodium-dependent glutathione transporter has been identified in the brain capillaries [ 43 ] and brain endothelial cells [ 44 ]. This provides a biological explanation for our observations of the association between glutathione and cognition. We did not demonstrate an association between CRP and cognitive decline in this population, apart from the baseline association with working memory performance where the association was borderline significant. Increased CRP, a marker of increased systemic inflammation, may occur later in the evolution of cognitive decline with aging and in neurodegeneration [ 48 ]. Further, peripheral CRP is a surrogate marker but not causative inflammatory mediator, thus we cannot exclude the possibility that decreased serum levels of glutathione are mirrored by simultaneous increased levels of inflammatory mediators in the CNS which in turn are linked to cognitive decline. Strengths of our study are the inclusion of healthy disease-free middle-aged individuals, the assessment of blood aminothiols as unique markers of OS, and detailed cognitive testing. The limitation of our study is relatively short follow-up period and the lack of brain imaging. The differential effects between peripheral and tissue may explain the lack of coupling between GSH and GSSG. Finally, additional oxidative stress markers from lipid and nucleic acid were not measured. OS reflected by a low or a progressive decrease in glutathione levels is associated with a decline in executive function with aging. The role of OS in cognitive decline offers further insights into the processes of cognitive aging and the link with vascular risk factors and warrants further investigation. Hatanaka H, Hanyu H, Hirose D, Fukusawa R, Namioka N, Iwamoto T. J Am Geriatr Soc. Article PubMed Google Scholar. Csanyi G, Miller FJ Jr. Oxidative stress in cardiovascular disease. Int J Mol Sci. Article CAS PubMed PubMed Central Google Scholar. White A, Culmsee C, Beart P. Oxidative stress and neurodegeneration. Neurochem Int. Article CAS PubMed Google Scholar. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Veal E, Day A. 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Chan KL, Puts NA, Schär M, Barker PB, Edden RA. HERMES: hadamard encoding and reconstruction of MEGA-edited spectroscopy. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer's disease. Download references. We are grateful to Dr. Mateusz Maciejczyk for providing additional data in the analysis of blood GSH in AD. Neuropsychopharmacology Research Group, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Bayview Avenue, Room FG52, Toronto, ON, M4N 3M5, Canada. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. Jinghan Jenny Chen, Mathura Thiyagarajah, Ana C. Department of Psychiatry, University of Toronto, Toronto, ON, Canada. Nathan Herrmann, Damien Gallagher, Mark J. Geriatric Psychiatry, Sunnybrook Health Sciences Centre, Toronto, ON, Canada. Evaluative Clinical Sciences, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada. Sandra E. KITE-Toronto Rehabilitation Institute, University Health Network, Toronto, ON, Canada. Physical Sciences, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON, Canada. You can also search for this author in PubMed Google Scholar. Study conception: NH, KL, and JC. Data collection: JC, MT, JS, and CC. Data analysis: JC. Data interpretation: JC, NH, and KL. Manuscript drafting: JC, NH, and KL. Manuscript editing and revision: JC, NH, SB, JR, AA, PO, SM, DG, MJR, SG, and KL. The authors read and approved the final manuscript. Correspondence to Krista L. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplemental table 1. PRISMA Checklist - Altered central and blood glutathione in Alzheimer Disease and Mild Cognitive Impairment: a meta-analysis. Open Access This article is licensed under a Creative Commons Attribution 4. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Reprints and permissions. Chen, J. et al. Alz Res Therapy 14 , 23 Download citation. Received : 15 April Accepted : 06 January Published : 05 February Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Rapoport 3 , 4 , Sandra E. Black 5 , 6 , Joel Ramirez 5 , Ana C. Andreazza 2 , Paul Oh 6 , Susan Marzolini 6 , Simon J. Lanctôt ORCID: orcid. Abstract Background Increasing evidence implicates oxidative stress OS in Alzheimer disease AD and mild cognitive impairment MCI. Aim To quantitatively review in vivo GSH in AD and MCI compared to healthy controls HC using meta-analyses. Method Studies with in vivo brain or blood GSH levels in MCI or AD with a HC group were identified using MEDLINE, PsychInfo, and Embase —June Conclusion Blood intracellular GSH decrease is seen in MCI, while both intra- and extracellular decreases were seen in AD. Methods Data sources The methodology outlined by the PRISMA guidelines was used for this review [ 24 ]. Table 1 Sample search strategy for Embase Full size table. Results Literature search Brain GSH literature findings The search returned unique records Fig. Search and selection of articles relevant to brain GSH in AD and MCI. Full size image. Table 2 Summary of included studies Full size table. Table 3 Study quality and risk of bias assessment. Search and selection of articles relevant to blood GSH in AD and MCI. |
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