Novel Blood-Based Biomarkers of Cognition, Stress, and Physical or Cognitive Training in Older Adults at Risk of Dementia: Preliminary Evidence for a Role of BDNF, Irisin, and the Kynurenine Pathway.
TL;DR: It is suggested that psychosocial stress as well as cognitive and physical training may impact BDNF serum levels and the KP, and Irisin and QUIN may constitute novel serum biomarkers of cognitive impairment, in addition to BDNF.
Abstract: Psychosocial stress and physical, cognitive, and social activity predict the risk of cognitive decline and dementia. The aim of this study was to elucidate brain-derived neurotrophic factor (BDNF), irisin, and the kynurenine pathway (KP) as potential underlying biological correlates. We evaluated associations of irisin and the KP with BDNF in serum and with cognition, stress, and activities. Furthermore, changes in serum concentrations of BDNF, irisin, and KP metabolites were investigated after physical or cognitive training. Forty-seven older adults at risk of dementia were assigned to 10 weeks of physical training, cognitive training, or a wait-list control condition. Previous physical, cognitive, and social activities and stressful life events were recorded; global cognition, episodic memory, and executive functions were assessed. Serum levels of L-kynurenine, kynurenic acid, 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN) were determined by validated assays based on liquid chromatography coupled to tandem mass spectrometry. BDNF and irisin serum levels were determined with enzyme-linked immunosorbent assays. BDNF and irisin correlated positively with global cognition and episodic memory, while the neurotoxic metabolite QUIN correlated negatively with executive functions. Stressful life events were associated with reduced BDNF and increased 3-HK. 3-HK decreased after cognitive training, while BDNF tended to increase after physical training. This suggests that psychosocial stress as well as cognitive and physical training may impact BDNF serum levels and the KP. Irisin and QUIN may constitute novel serum biomarkers of cognitive impairment, in addition to BDNF. Larger scale trials are needed to replicate and extend these novel findings.
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TL;DR: This review provides a broad overview of the mechanistic pathways through which the kynurenines interact with multiple physiological systems that are commonly disrupted in psychiatric disorders, including endocrine, metabolic, and hormonal systems, thus impacting emotion, cognition, pain, metabolic function, and aging, and in so doing potentially increasing the risk of developing psychiatric disorders.
Abstract: The kynurenine pathway (KP) plays a critical role in generating cellular energy in the form of nicotinamide adenine dinucleotide (NAD+). Because energy requirements are substantially increased during an immune response, the KP is a key regulator of the immune system. Perhaps more importantly in the context of psychiatry, many kynurenines are neuroactive, modulating neuroplasticity and/or exerting neurotoxic effects in part through their effects on NMDA receptor signaling and glutamatergic neurotransmission. As such, it is not surprising that the kynurenines have been implicated in psychiatric illness in the context of inflammation. However, because of their neuromodulatory properties, the kynurenines are not just additional members of a list of inflammatory mediators linked with psychiatric illness, but in preclinical studies have been shown to be necessary components of the behavioral analogs of depression and schizophrenia-like cognitive deficits. Further, as the title suggests, the KP is regulated by, and in turn regulates multiple other physiological systems that are commonly disrupted in psychiatric disorders, including endocrine, metabolic, and hormonal systems. This review provides a broad overview of the mechanistic pathways through which the kynurenines interact with these systems, thus impacting emotion, cognition, pain, metabolic function, and aging, and in so doing potentially increasing the risk of developing psychiatric disorders. Novel therapeutic approaches targeting the KP are discussed. Moreover, electroconvulsive therapy, ketamine, physical exercise, and certain non-steroidal anti-inflammatories have been shown to alter kynurenine metabolism, raising the possibility that kynurenine metabolites may have utility as treatment response or therapeutic monitoring biomarkers.
288 citations
TL;DR: Biomarker panels for frailty would be of high value and better than single markers.
267 citations
Cites background from "Novel Blood-Based Biomarkers of Cog..."
...Irisin also correlated positively with global cognition and contributes to the neuroprotective effect of exercise (Kuster et al., 2017; Li et al., 2017a; Wrann et al., 2013)....
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TL;DR: Irisin reduces systemic inflammation, maintains the balance between resorption and bone formation, and modulates metabolic processes and the functioning of the nervous system, and may be a potential option to prevent and treat civilization-related diseases.
Abstract: Sedentary life style is considered to be an independent risk factor for many disorders, including development of type 2 diabetes, obesity, immune dysfunction, asthma, and neurological or coronary heart disease. Irisin is released from myocytes during physical activity, and acts as a link between muscles and other tissues and organs. This myokine is produced as a result of proteolytic cleavage of FNDC5 protein present in the membrane of myocytes. Secretion of irisin is regulated by N-linked oligosaccharides attached to the protein molecule. The two N-glycan molecules, which constitute a significant part of the irisin glycoprotein, regulate the browning of adipocytes, which is the most important function of irisin. A receptor specific for irisin has still not been discovered. In some tissues irisin probably acts via integrins, which are widely expressed transmembrane receptors. Many studies have confirmed the multifunctional role of irisin and the beneficial effects of this molecule on body homeostasis. Irisin reduces systemic inflammation, maintains the balance between resorption and bone formation, and modulates metabolic processes and the functioning of the nervous system. It suppresses the expression and release of pro-inflammatory cytokines in obese individuals and attenuates inflammation in adipose tissue. The impact of irisin on cancer cell proliferation, migration, and invasion has also been demonstrated in numerous studies, which proves its role in carcinogenesis. Owing to these pleiotropic and beneficial properties, irisin may be a potential option to prevent and treat civilization-related diseases which are, nowadays, considered to be the major health problems in Western societies.
86 citations
Cites background from "Novel Blood-Based Biomarkers of Cog..."
...A positive correlation between serum irisin and BDNF levels, and cognition and episodic memory was observed after 10 weeks of physical training in adult volunteers at risk of dementia [49]....
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TL;DR: This review will focus on FNDC5 and its secreted form, the newly discovered myokine "irisin", and their role in the beneficial effects of exercise and its potential application in neurodegenerative disorders.
69 citations
TL;DR: More than 1000 papers have been published exploring the roles of irisin. as mentioned in this paper reviewed the current knowledge and delineate potential solutions to resolve existing ambiguities, and a promising new tool has been developed-mice with a global or tissue-specific knockout of FNDC5.
Abstract: In 2002, a transmembrane protein-now known as FNDC5-was discovered and shown to be expressed in skeletal muscle, heart, and brain. It was virtually ignored for 10 years, until a study in 2012 proposed that, in response to exercise, the ectodomain of skeletal muscle FNDC5 was cleaved, traveled to white adipose tissue, and induced browning. The wasted energy of this browning raised the possibility that this myokine, named irisin, might mediate some beneficial effects of exercise. Since then, more than 1000 papers have been published exploring the roles of irisin. A major interest has been on adipose tissue and metabolism, following up the major proposal from 2012. Many studies correlating plasma irisin levels with physiological conditions have been questioned for using flawed assays for irisin concentration. However, experiments altering irisin levels by injecting recombinant irisin or by gene knockout are more promising. Recent discoveries have suggested potential roles of irisin in bone remodeling and in the brain, with effects potentially related to Alzheimer's disease. We discuss some discrepancies between research groups and the mechanisms that are yet to be determined. Some important questions raised in the initial discovery of irisin, such as the role of the mutant start codon of human FNDC5 and the mechanism of ectodomain cleavage, remain to be answered. Apart from these specific questions, a promising new tool has been developed-mice with a global or tissue-specific knockout of FNDC5. In this review, we critically examine the current knowledge and delineate potential solutions to resolve existing ambiguities.
56 citations
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TL;DR: A simplified, scored form of the cognitive mental status examination, the “Mini-Mental State” (MMS) which includes eleven questions, requires only 5-10 min to administer, and is therefore practical to use serially and routinely.
76,181 citations
01 Jan 2002
TL;DR: The Mini-Mental State (MMS) as mentioned in this paper is a simplified version of the standard WAIS with eleven questions and requires only 5-10 min to administer, and is therefore practical to use serially and routinely.
Abstract: EXAMINATION of the mental state is essential in evaluating psychiatric patients.1 Many investigators have added quantitative assessment of cognitive performance to the standard examination, and have documented reliability and validity of the several “clinical tests of the sensorium”.2*3 The available batteries are lengthy. For example, WITHERS and HINTON’S test includes 33 questions and requires about 30 min to administer and score. The standard WAIS requires even more time. However, elderly patients, particularly those with delirium or dementia syndromes, cooperate well only for short periods.4 Therefore, we devised a simplified, scored form of the cognitive mental status examination, the “Mini-Mental State” (MMS) which includes eleven questions, requires only 5-10 min to administer, and is therefore practical to use serially and routinely. It is “mini” because it concentrates only on the cognitive aspects of mental functions, and excludes questions concerning mood, abnormal mental experiences and the form of thinking. But within the cognitive realm it is thorough. We have documented the validity and reliability of the MMS when given to 206 patients with dementia syndromes, affective disorder, affective disorder with cognitive impairment “pseudodementia”5T6), mania, schizophrenia, personality disorders, and in 63 normal subjects.
70,887 citations
TL;DR: A new Geriatric Depression Scale (GDS) designed specifically for rating depression in the elderly was tested for reliability and validity and compared with the Hamilton Rating Scale for Depression (HRS-D) and the Zung Self-Rating Depression Scale(SDS) as discussed by the authors.
13,014 citations
TL;DR: It is shown that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory, and that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus.
Abstract: The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.
3,616 citations
TL;DR: This article showed that PGC1α expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin.
Abstract: Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-γ co-activator-1 α (PGC1-α). Here we show in mouse that PGC1-α expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise.
3,338 citations