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Beneficial Effects of Glycine (Bioglycin) on Memory and Attention in Young and Middle-Aged Adults
Abstract
The N-methyl D-aspartate receptor complex is involved in the mechanism of long-term potentiation, which is thought to be the biological basis of learning and memory. This complex can be manipulated in a number of ways, one of which is through the strychnine-insensitive glycine receptor coagonist site. The effects of Bioglycin(Konapharma, Pratteln, Switzerland), a biologically active form of the amino acid glycine, were therefore studied in healthy students (mean age, 20.7 years) and middle-aged men (mean age, 58.9 years) with tests that measured attention, memory and mood, using a double-blind, randomized, crossover design. Compared with the young group, the middle-aged group had significantly poorer verbal episodic memory, focused, divided, and sustained attention; they also differed in their subjective responses at the end of testing. Bioglycin significantly improved retrieval from episodic memory in both the young and the middle-aged groups, but it did not affect focused or divided attention. However, the middle-aged men significantly benefited from Bioglycin in the sustained-attention task. The effects of Bioglycin differed from those of other cognitive enhancers in that it was without stimulant properties or significant effects on mood, and it primarily improved memory rather than attention. It is likely to be of benefit in young or older people in situations where high retrieval of information is needed or when performance is impaired by jet lag, shift work, or disrupted sleep. It may also benefit the impaired retrieval shown in patients with schizophrenia, Parkinson's disease, and Huntington's disease.
... Previous study publicized that ingestion of dietary L-arginine, L-leucine, L-cysteine, L-cysteine-HCl, L-glycine and L-methionine could have positive influence against vasoconstriction, hypertension, blood pressure, high cholestrol level, cardiac and cardiovascular problems 20,[27][28][29][30][31][32][33][34][35][36][37][38][39] . L-arginine, L-leucine, L-lysine, L-cysteine, L-phenylalanine, L-glycine are also anti-hyperglycemic, anti-hyperlipidermic, anti-diabetic and therapeutically potential against insulin resistant 20,26,[39][40][41][42][43] . CNS complication and impaired cognition viz. ...
... CNS complication and impaired cognition viz. dementia, elevated level of catecholamine, neurotoxin deoxysphingolipids (the constituent of myelin surrounding the axon) as well as neuron's firing, sleep disorder (insomnia), memory/dementia, adverse mood, emotional/mental problem, learning inefficiency, Alzheimer's dementia, spastic and schizophrenia disorder could be declined by the intake of L-phenylalanine/tyrosine L-arginine, L-lysine, L-leucine, L-Histidine, L-threonine, L-methionine, L-serine, L-glycine and L-proline cocktail 10,19,24,25,29,40,[43][44][45][46][47][48][49][50][51][52] . Ingestion of L-phenylalanine/tyrosine, L-cysteine, L-glycine, L-methionine supplement can boost energy (GSH) level 49 , whereas L-histidine and L-ornithine content diminish fatigue after/during exposure to stressors 51,53 . ...
The high altitude trans-Himalayan region indeed is hostile domain for survival. Algae inhabiting this hostile terrain have evolutionarily developed mechanisms to produce unique adaptogenic molecules against climatic stressors. The present study has focused on the high altitude alga Spirogyra porticalis (Muell.) Cleve- a filamentous Charophyte, and reports the estimation of amino acids (AAs), fatty acids (FAs), vitamins and their efficacy against oxidative stress. Reverse phase-HPLC, GC-FID and rapid resolution-LC/tandem mass spectrometry were used for analysis of AAs, FAs and vitamins. Analysis of the alga revealed the presence of 19 AAs (239.51 ± 8.57 to 13102.40 ± 11.08 µg/g), dominated by alanine, proline and lysine. Enriched phenylalanine, cysteine-HCl and high lysine:arginine ratio could also have beneficial impact against hypoxia -induced cognitive impairment. A total of 9 FAs were detected (0.43 ± 0.00% to 34.76 ± 0.52%). Polyunsaturated and monounsaturated FAs were found to be dominant. The alga showed the presence of 8 vitamins within the range of 39.654 ± 3.198 to 5468.184 ± 106.859 µg/Kg, wherein Vitamin B5, B3 and B2 were dominant. 600 µg/ml of methanolic extract showed recovery of GSH and trolox equivalent antioxidants in rat blood/hemolysate, while 400 µg/ml of extract showed revival in superoxide dismutase (SOD) activity. The present study concludes that the alga S. porticalis has immense potential to counter oxidative stress as a nutraceutical supplement.
... This is likely related to individual differences in study design, small samples, and ranges in dose. [29][30][31][32] Glycine transport across the blood-brain barrier is low, but CSF levels can be influenced in a dose-dependent manner by moderateto-high doses. 33 A 2010 meta-analysis of studies with glycinergic coagonists for the treatment of schizophrenia included an analysis of the dose-response of glycine based on 10 studies for this indication. ...
... The effect of glycine on cognitive tasks has been inconsistent, possibly related to differences in dosing and treatment conditions. [30][31][32] In a study 18 of patients with chronic regional pain syndrome 1, intrathecal glycine was given to 19 patients eligible for intrathecal baclofen treatment in a doubleblind placebo-controlled crossover study. The dose was started at 8 mg/24 h and increased weekly by 8 mg/24 h to 32 mg/24 h in the fourth week. ...
Glycine and related endogenous compounds (d-serine, d-alanine, sarcosine) serve critical roles in both excitatory and inhibitory neurotransmission and are influenced by a multitude of enzymes and transporters, including glycine transporter 1 and 2 (GlyT1 and GlyT2), d-amino acid oxidase (DAAO), serine racemase (SRR), alanine-serine-cysteine transporter 1 (Asc-1), and kynurenine aminotransferase (KAT). MEDLINE, Web of Science, and PsychINFO were searched for relevant human trials of compounds. Many studies utilizing exogenous administration of small molecule agonists of the glycineB site of n-methyl-d-aspartate receptor have been studied as have a growing number of glycine transporter type 1 (GlyT1) inhibitors. The clinical effects of these compounds are reviewed as are the potential effects of newer novel compounds.
... One study has investigated the effects of intravenous glycine (0.1 or 0.2 g/kg) on healthy controls and failed to find an effect on behavioral measures, cognitive functioning, or acoustic startle response (D'Souza et al. 2000). Several studies using drugs that stimulate glycine neurotransmission, for instance 0.1 g of Bioglycin (a biologically active form of glycine; File et al. 1999) and 0.4 and 1.2 g of milacemide (a glycine precursor; Saletu and Grunberger 1984;Schwartz et al. 1991), have demonstrated improvements in memory and vigilance tasks, while a subsequent study found no effects with 0.4 g of milacemide (Camp-Bruno and Herting 1994). Thus, we are not in a position to comment on the cognitive effects of high doses, as previously employed for AGT in patients with schizophrenia. ...
... However, to reduce the complexity of the current study, one single dose was utilised. The time of electrophysiological recording was chosen to coincide with the maximum glycine plasma concentration, which has been reported to peak at approximately 30-45 min (Truong and Fahn 1988;Gannon et al. 2002) and cognitive and electrophysiological effects reported within this time window (File et al. 1999). ...
NMDA receptor hypofunction, indexed by reduced mismatch negativity (MMN), is proposed to underlie deficits in early auditory processing in schizophrenia (SCZ). Glycine increases NMDA neurotransmission and has been reported to improve functioning as an adjunct to antipsychotic medication. The effects of glycine on MMN in SCZ are unknown and warrant further investigation. Duration (100ms; Standards 50ms, 100Hz, 80dB) and frequency (1100Hz) MMN were compared, at baseline, between 23 participants with a primary diagnosis of SCZ or schizoaffective disorder and 21 matched controls. MMN was reassessed in the patient group after administration of either 0.2g/kg glycine or placebo. Patients were rated on the Positive and Negative Syndrome Scale (PANSS) at baseline and provided blood samples pre- and post-glycine administration to monitor glycine serum levels. At baseline, duration MMN was reduced in SCZ compared to controls (p=.002), but frequency MMN was reduced at trend level only (p=.065). Smaller duration MMN at baseline was associated with greater PANSS negative symptoms (p=.023) in patients. The difference between pre- and post-treatment duration MMN was increased after glycine when compared to placebo (p=.009); that is, glycine increased MMN. No difference was observed for frequency MMN and correlations between MMN and glycine serum were not found. These findings suggest that duration MMN is associated with negative symptoms and that acute (0.2g/kg) glycine increases duration MMN in SCZ. Our findings offer insight into the pathophysiology of reduced MMN in SCZ. MMN is a latent biomarker of NMDA function and further research should determine whether prolonged glycine treatment ameliorates reduced MMN in SCZ.
... One study has investigated the effects of intravenous glycine (0.1 or 0.2 g/kg) on healthy controls and failed to find an effect on behavioral measures, cognitive functioning, or acoustic startle response (D'Souza et al. 2000). Several studies using drugs that stimulate glycine neurotransmission, for instance 0.1 g of Bioglycin (a biologically active form of glycine; File et al. 1999) and 0.4 and 1.2 g of milacemide (a glycine precursor; Saletu and Grunberger 1984;Schwartz et al. 1991), have demonstrated improvements in memory and vigilance tasks, while a subsequent study found no effects with 0.4 g of milacemide (Camp-Bruno and Herting 1994). Thus, we are not in a position to comment on the cognitive effects of high doses, as previously employed for AGT in patients with schizophrenia. ...
... However, to reduce the complexity of the current study, one single dose was utilised. The time of electrophysiological recording was chosen to coincide with the maximum glycine plasma concentration, which has been reported to peak at approximately 30-45 min (Truong and Fahn 1988;Gannon et al. 2002) and cognitive and electrophysiological effects reported within this time window (File et al. 1999). ...
An impaired capacity to filter or ‘gate’ sensory information is a core deficit in cognitive function associated with schizophrenia. These deficits have been linked in part to N-methyl-d-aspartate (NMDA) receptor dysfunction. An association between high levels of glycine, a positive allosteric modulator of the NMDA receptor, and sensorimotor gating impairments (i.e. prepulse inhibition (PPI) deficit) have been reported in animal models of schizophrenia as well as patients with schizophrenia.
This study examined the acute effects of modulating the glycine site of the NMDA receptor (with high-dose glycine) on sensory gating as measured by PPI. Sixteen healthy male subjects (final sample size of 12) participated in a double-blind, placebo-controlled, crossover design in which each subject was tested under two acute treatment conditions separated by at least a 5-day washout period; placebo and 0.8 g/kg glycine. PPI was recorded 45 min post treatment using electromyography of the eye-blink response.
Relative to placebo, high-dose glycine significantly impaired sensorimotor gating as demonstrated by a decrease in PPI ( t(11) = −2.983, p < 0.05).
Administration of a high dose of glycine is associated with impairments in PPI supporting earlier observations in animals and patients with schizophrenia. This result, when taken together with findings in patients, suggests that high synaptic levels of glycine may have some clinically relevant detrimental effects and suggests a potential dissociation of clinical symptomatology and sensory information processing as a function of NMDA receptor modulation in schizophrenia.
... agoraphobia, social anxiety, obsessive-compulsive disorder) in humans (Norberg et al. 2008). Administration of both glycine (File et al. 1999) and DCS (Schwartz et al. 1996 ;Tsai et al. 1999) as continuous pharmacotherapy unrelated to cognitive-behavioural interventions was found to enhance memory in some human studies. Furthermore, in some clinical trials glycine and DSR, applied as adjuvant continuous treatment, reduce negative and cognitive symptoms severity in treatment-resistant schizophrenia patients (Heresco-Levy, 2005). ...
... Clinical findings with different subject populations suggest that enhancement of NMDAR function obtained by treatment with amino acids (i.e. glycine, DSR) that act as endogenous allosteric modulators of the NMDAR glycine site may alleviate anxiety, negative and cognitive symptoms (File et al. 1999 ;Greenberg et al. 2007 ;Heresco-Levy, 2005). Furthermore, evidence for an anxiolytic potential of glycine reuptake inhibitors, was obtained using animal anxiety models (Depoortère et al. 2005). ...
Enhancement of neurotransmission mediated at N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) may be beneficial in post-traumatic stress disorder (PTSD). d-serine (DSR) is an endogenous full agonist at the NMDAR-associated glycine modulatory site. Twenty-two chronic PTSD outpatients were randomly assigned to participate in a 6-wk double-blind, placebo-controlled, crossover trial with 30 mg/kg x d DSR used as monotherapy or add-on pharmacotherapy. Outcome was assessed using the Clinician-Administered PTSD scale (CAPS), Hamilton Anxiety (HAMA) and Depression (HAMD) scales and the civilian version of the Mississippi Scale for Combat-Related PTSD (MISS). DSR treatment was well tolerated and resulted in significantly (p=0.03) increased DSR serum levels. Compared with placebo administration, DSR treatment resulted in significantly reduced HAMA (p=0.007) and MISS (p=0.001) scores and a trend (p=0.07) towards improved CAPS total scores. These preliminary findings indicate that NMDAR glycine site-based pharmacotherapy may be effective in PTSD and warrant larger-sized clinical trials with optimized DSR dosages.
... Glycine has many potential health benefits such as improving sleep, elevating mood, and lowering the risk of heart disease (79)(80)(81). Glycine is found in many protein-based food sources and is used as a food additive or taken as supplements. However, the long-term safety of glycine supplements, such as their effects on plasma or CSF glycine levels, has not been fully tested. ...
Adolescent idiopathic scoliosis (AIS) is the most common form of spinal deformity affecting millions of adolescents worldwide, but it lacks a defined theory of etiopathogenesis. As such, treatment of AIS is limited to bracing and/or invasive surgery post onset. Pre-onset diagnosis or preventive treatment remains unavailable. Here we performed a genetic analysis of a large multi-center AIS cohort and identified disease-causing and predisposing variants of SLC6A9 in multi-generation families, trios, and sporadic patients. Variants of SLC6A9, which encodes glycine transporter 1 (GLYT1), reduced glycine uptake activity in cells, leading to an increased extracellular glycine level and aberrant glycinergic neurotransmission. Slc6a9 mutant zebrafish exhibited discoordination of spinal neural activities and pronounced lateral spinal curvature, a phenotype resembling human patients. The penetrance and severity of curvature was sensitive to the dosage of functional glyt1. Administration of a glycine receptor antagonist or a clinically-used glycine neutralizer (sodium benzoate) partially rescued the phenotype. Our results indicate a neuropathic origin for "idiopathic" scoliosis, involving the dysfunction of synaptic neurotransmission and central pattern generators (CPGs), potentially a common cause of AIS. Our work further suggests avenues for early diagnosis and intervention of AIS in preadolescents.
... In mice, prolyl-hydroxyproline peptides, derived from oral collagen hydrolysate ingestion, stimulated neurogenesis in the hippocampus [25,26,84], a brain region that contributes to cognitive function [85]. In addition, glycine alone has been shown to improve cognition in some studies [86,87], ostensibly by activating NMDA receptors, now a promising target in mood disorders [88]. Therefore, we cannot rule out that CP enhanced cognitive performance, independent of the differences in sleep fragmentation. ...
Purpose
The primary aim of this study was to examine whether a glycine-rich collagen peptides (CP) supplement could enhance sleep quality in physically active men with self-reported sleep complaints.
Methods
In a randomized, crossover design, 13 athletic males (age: 24 ± 4 years; training volume; 7 ± 3 h·wk ¹ ) with sleep complaints (Athens Insomnia Scale, 9 ± 2) consumed CP (15 g·day ¹ ) or a placebo control (CON) 1 h before bedtime for 7 nights. Sleep quality was measured with subjective sleep diaries and actigraphy for 7 nights; polysomnographic sleep and core temperature were recorded on night 7. Cognition, inflammation, and endocrine function were measured on night 7 and the following morning. Subjective sleepiness and fatigue were measured on all 7 nights. The intervention trials were separated by ≥ 7 days and preceded by a 7-night familiarisation trial.
Results
Polysomnography showed less awakenings with CP than CON (21.3 ± 9.7 vs. 29.3 ± 13.8 counts, respectively; P = 0.028). The 7-day average for subjective awakenings were less with CP vs. CON (1.3 ± 1.5 vs. 1.9 ± 0.6 counts, respectively; P = 0.023). The proportion of correct responses on the baseline Stroop cognitive test were higher with CP than CON (1.00 ± 0.00 vs. 0.97 ± 0.05 AU, respectively; P = 0.009) the morning after night 7. There were no trial differences in core temperature, endocrine function, inflammation, subjective sleepiness, fatigue and sleep quality, or other measures of cognitive function or sleep (P > 0.05).
Conclusion
CP supplementation did not influence sleep quantity, latency, or efficiency, but reduced awakenings and improved cognitive function in physically active males with sleep complaints.
... Glycine serves primarily as an inhibitory neurotransmitter in the CNS (75). It generally improves mood, mental performance and memory skills (76,77). However, elevated levels can compromise cognitive processing and provoke seizures (78,79). ...
Epilepsy is the most common chronic neurological disease in humans and dogs. Epilepsy is thought to be caused by an imbalance of excitatory and inhibitory neurotransmission. Intact neurotransmitters are transported from the central nervous system to the periphery, from where they are subsequently excreted through the urine. In human medicine, non-invasive urinary neurotransmitter analysis is used to manage psychological diseases, but not as yet for epilepsy. The current study aimed to investigate if urinary neurotransmitter profiles differ between dogs with epilepsy and healthy controls. A total of 223 urine samples were analysed from 63 dogs diagnosed with idiopathic epilepsy and 127 control dogs without epilepsy. The quantification of nine urinary neurotransmitters was performed utilising mass spectrometry technology. A significant difference between urinary neurotransmitter levels (glycine, serotonin, norepinephrine/epinephrine ratio, ɤ-aminobutyric acid/glutamate ratio) of dogs diagnosed with idiopathic epilepsy and the control group was found, when sex and neutering status were accounted for. Furthermore, an influence of antiseizure drug treatment upon the urinary neurotransmitter profile of serotonin and ɤ-aminobutyric acid concentration was revealed. This study demonstrated that the imbalances in the neurotransmitter system that causes epileptic seizures also leads to altered neurotransmitter elimination in the urine of affected dogs. Urinary neurotransmitters have the potential to serve as valuable biomarkers for diagnostics and treatment monitoring in canine epilepsy. However, more research on this topic needs to be undertaken to understand better the association between neurotransmitter deviations in the brain and urine neurotransmitter concentrations in dogs with idiopathic epilepsy.
... The N-methyl D-aspartate receptor is associated with the long-term potentiation, which is considered as the biological mechanism of learning and memory. This mechanism is mediated through glycine receptor co-agonist site (File et al., 1999). The positive effects of glycine doses were observed in patients with schizophrenia (https://clinicaltrials.gov/ct2/show/NCT005 75848). ...
Glycine is an important chemical mediator of nervous system that plays a vital role in memory and other neurological functions. Therefore, the effect of glycine on these traits must be studied to understand biological mechanisms of intricate neurological system. We investigated the effect of different doses of glycine on memory and behavior using 30 albino mice models (treated and control). After two weeks of glycine dosing, we performed light and dark activity and novel-object recognition (NOR) tests to assess the cognitive traits. Brain and blood samples were taken and kept at-70°C using ultra-low temperature freezer. Neurochemical estimation of blood glycine level was estimated by high-performance liquid chromatography with electrochemical detectors (HPLC-ECD). Concentration of glycine (100, 300 and 500 mg/kg) is significantly observed (p<0.01) and it changes due to physiological variations in N-methyl-D-aspartate (NMDA) an important neurotransmitter for memory. We observed significant increase in serotonin metabolites including 5-hydroxy tryptophan (5-HT, p<0.05) and 5-hydroxy indole acetic acid (5-HIAA, p<0.001) levels. Similarly, effects were found in case of dopamine (DA, p<0.05) and its metabolites: 3, 4-Dihydroxyphenylacetic acid (DOPAC, p<0.001) and homovanillic acid (HVA, p<0.001). Histopathological investigation of brain tissues showed cellular clumps at cortical junctions at higher doses of glycine as compared to control. These findings revealed that dose dependent concentration of glycine can be useful for memory loss and behavior deficits.
... This latter effect appears to be mediated by interference with activation of nuclear factor kappa B (NFκB) [19]. In humans, oral glycine has been already employed for treatment of some diseases, apparently without side effects [20][21][22]. Commercial glycine is a watersoluble, crystalline white powder with a moderately sweet flavor and is relatively inexpensive (about $20 US dollars per kg in Mexico). ...
Background:
Patients with cystic fibrosis (CF) have airway inflammation that contributes to symptoms and to pulmonary function derangement. Current drugs used to diminish airway inflammation improve the clinical and spirometric status of patients with CF, but their use is limited due to their undesired side effects, for example, glucose intolerance, growth retardation, and cataracts with corticosteroids, gastrointestinal toxicity with ibuprofen, and macrolide resistance with azythromycin. Glycine is known to decrease activation of inflammatory cells, including alveolar macrophages and neutrophils, and is relatively inexpensive, palatable, and virtually devoid of untoward effects. These features make glycine a good candidate for antiinflammatory treatment of CF. Thus, we aimed to explore whether glycine can exert a beneficial effect in a population of patients with CF.
Methods:
This was a randomized, double blinded, cross-over pilot clinical trial. Subjects with CF received, in random order, oral glycine (0.5 g/kg/day, dissolved in any liquid) and placebo (glass sugar), each during 8 weeks with an intermediate 2-week wash-out period.
Results:
Thirteen subjects aged 6-23 years, 8 females, completed the two arms of the study. As compared with placebo, after glycine intake patients had better symptom questionnaire scores (p = 0.02), mainly regarding sputum features and dyspnea. While spirometric variables tended to decline during placebo intake, they remained stable or even increased during glycine treatment (p = 0.04 to p = 0.003). In this context, FEV1 declined 8.6% after placebo and increased 9.7% at the end of the glycine period. Pulse oximetry improved after glycine intake (p = 0.04 vs. placebo). TNF-α in serum and IL-6 and G-CSF in sputum tended to decline at the end of the glycine period (p = 0.061, p = 0.068 and p = 0.04, respectively, vs placebo). Glycine was remarkably well tolerated.
Conclusions:
The clinical, spirometric and inflammatory status of subjects with CF improved after just 8 weeks of glycine intake, suggesting that this amino acid might constitute a novel therapeutic tool for these patients. Thus, further studies are warranted.
Trial registration:
www.clinicaltrials.gov , registration number: NCT01417481 , date of registration: March 12, 2012.
... These have included targeting glucocorticoid (e.g. De Bitencourt et al., 2013), glutamtergic (Kuriyama et al., 2013), GABAergic (Rodríguez et al., 2013) adrenergic (Kindt et al., 2009), cannabinoid (Rabinak et al., 2013), serotonergic (Zhang et al., 2013) and glycine (File et al., 1999) receptors. Research on disrupting memory derives predominately from studying Pavlovian fear conditioning using an electrical shock. ...
... For example, bioglycin is an orally active form of glycine that was studied in much lower doses than those used with glycine. In a doubleblind crossover design study, one dose of 2 mg/kg of Bioglycin significantly improved episodic memory in both healthy young adults and middle-aged men (mean age, 59 years), and improved sustained-attention only in the group of middle-aged men [102]. In contrast, in another crossover design study, one high dose of glycine (800 mg/kg) did not improve memory, attention or perceptual processing in young healthy subjects [103]. ...
The world population is growing older and age-related cognitive decline is becoming a burden of societal importance. D-serine is an endogenous amino acid that activates the co-agonist site of the NMDA-glutamate receptor, which is related to cognitive functions, such as learning and memory. Studies in aged rodents have shown a marked decrease in the levels of D-serine in brain regions such as the hippocampus, a key region for encoding memory. Exogenous administration of D-serine in rodents has demonstrated pro-cognitive effects in several brain functions, including memory and executive function. Further to animal studies, our group has observed an age-related decrease in D-serine in the blood of healthy adults and elderly. The oral administration of D-serine induced significant improvement in executive function and spatial problem solving in elderly, some of the key cognitive domains affected by aging. In this review we propose the activation of the co-agonist site of NMDA receptors as a target to remediate features of the age-related cognitive decline. The cognitive effects of other agents targeting the co-agonist site of NMDA receptors are also discussed.
... These have included targeting glucocorticoid (e.g. De Bitencourt et al., 2013), glutamtergic (Kuriyama et al., 2013), GABAergic (Rodríguez et al., 2013) adrenergic (Kindt et al., 2009), cannabinoid (Rabinak et al., 2013), serotonergic (Zhang et al., 2013) and glycine (File et al., 1999) receptors. ...
Here we provide a brief overview of recent research on memory manipulation. We focus primarily on memories for which the hippocampus is thought to be required due to its central importance in the study of memory. The repertoire of methods employed is expanding and includes optogenetics, transcranial stimulation, deep brain stimulation, cued reactivation during sleep and the use of pharmacological agents. In addition, the possible mechanisms underlying these memory changes have been investigated using techniques such as single unit recording and functional magnetic resonance imaging (fMRI)., This article is part of a Special Issue entitled 'Memory enhancement'.
... Similar effect was demonstrated for glycine which also induces weak lowering of plasma membrane potential in synaptosomes [41]. It can be noted that glycine like piracetam has nootropic properties [12,14]. High concentration of piracetam (1 mM) which I used in experiments was found in brain when therapeutic doses were applied [5]. ...
... Glycine works as an agonist at another type of receptor site in the central nervous system: the N-methyl-D-asparate (NMDA) receptor. NMDA receptors are associated with memory and learning 20 and are thought to play a role in both the negative and positive symptoms of schizophrenia. 21 Schizophrenia is thought to be associated with underactivity of glutamatergic receptors, especially the NMDA type. ...
Glutamine supplementation is a highly cost-effective treatment for patients who undergo cancer treatments. In addition to chemotherapy-induced anorexia, painful sores in the oral mucosa can make eating an unpleasant or even intol- erable experience for these patients who desperately need good nutrition during the course of therapy. Providing glutamine for such patients, and healing their mucositis, can improve their quality of life at a time when such support is much needed. It has been demonstrated that glutamine is found in reduced amounts in certain cancers.4 Coupled with the fact that GI cells are some of the most rapidly dividing cells in the body, and that chemotherapy (as a side-effect) targets these rapidly dividing cells, patients are at an increased risk of developing GI problems. Glutamine supplementation can help prevent GI toxicity induced by chemotherapy and radiation, thereby assisting normal GI function.5 Glutamine is a preferential metabolic substrate for the entero- cytes and is thought to play a regulatory role in the intestinal tis- sue by influencing cellular proliferation and differentiation.6 As a result, the GI tract is the largest consumer of glutamine in the body7; suboptimal dietary amounts of glutamine can lead to atrophic changes, including ulceration and necrosis of the intesti- nal tissue.
... N-methyl-D-aspartate (NMDA) receptors play an important role in learning and memory. Targeting the glycine modulatory site of the NMDA receptor has been suggested as a therapeutic strategy to improve cognition (Schwartz et al., 1991;File et al., 1999;Palmer et al., 2008). An acute high dosage of glycine attenuates mismatch negativity in healthy controls. ...
We carried out animal experiments based on the orthogonal design L(8)(2(7)) setting seven factors with two different levels of each and 10 groups of rats. The nutrients tested were tyrosine, glycine, methionine, taurine, ascorbic acid, thiamine and zinc.
The objective of this study was to explore the optimal combinations of nutrients for prevention or amelioration of lead-induced learning and memory impairment.
Rats were supplemented with nutrients by gavage once a day in two experiments: one was simultaneous nutrient supplementation with lead acetate administration (800 mg l(-1)) for 8 weeks (prophylactic supplementation) and the other was nutrient supplementation for 4 weeks after the cessation of 4 weeks of lead administration (remedial supplementation). Morris water maze was initiated at ninth week. Rats were terminated for assays of levels of Pb in blood, activities of superoxide dismutase (SOD) and nitric oxide synthase (NOS) in hippocampus, levels of nitric oxide (NO) in hippocampus and expressions of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and cyclic adenosine monophosphate (cAMP) response element-binding protein messenger RNA in hippocampus.
Results showed that in prophylactic supplementation, methionine, taurine, zinc, ascorbic acid and glycine were the effective preventive factors for decreasing prolonged escape latency, increasing SOD and NOS activities and NO levels in the hippocampus, respectively. On the other hand, in remedial supplementation, taurine was the effective factor for reversing Pb-induced decrease in activities of SOD, NOS and levels of NO.
In conclusion, the optimum combinations of nutrients appear to be methionine, taurine, zinc, ascorbic acid and glycine for the prevention of learning and memory impairment, while taurine and thiamine appear to be the effective factors for reversing Pb neurotoxicity.
... Milacemide, which in contrast to glycine has a greater therapeutic safety, did improve memory in elderly, but there was little therapeutic success in Alzheimer patients [180,458]. Bioglycine, a biologically active form of glycine, had no effect on mood or attention, but facilitated episodic memory in young and middle aged volunteers [140]. ...
The contribution of glutamate to synaptic transmission, plasticity and development is well established; current evidence is based on diverse approaches to decipher function and malfunction of this principal transmitter. With respect to learning and memory, we are now able to identify more specifically the role played by the three main glutamate receptor classes in learning and memory: centre stage is clearly the NMDA receptor, with overwhelming evidence proving its involvement in the actual learning process (encoding), throughout the animal kingdom. This is discussed with respect to many different types of learning. Evidence for the contribution of the AMPA receptors (AMPARs) is less clear-cut due to the general problem of specificity: block of AMPARs will shutdown neuronal communication, and this will affect various components essential for learning. Therefore, the role of AMPARs cannot be established in isolation. Problems of interpretation are outlined and a specific involvement of AMPARs in the regulation of neuronal excitation related to learning is proposed. Metabotropic glutamate receptors (mGluRs) may contribute very little to the actual acquisition of new information. However, memory formation appears to require mGluRs, through the modulation of consolidation and/or recall. Overall, mGluR functions seem variable and dependent on brain structure and learning task.
... This is mainly due to the very low variability in the students' scores, both within and between years (File et al., 2001a,b; 2002a). The former type of study design was also found to be sensitive to the cognitive-enhancing effects of glycine (File et al., 1999a). ...
Modafinil is a selective wakefulness-promoting agent with beneficial effects in narcolepsy and conditions of sleep deprivation. In a double-blind study we examined its effects in 30 healthy, non sleep-deprived students (19 men and 11 women, aged 19-23 years), who were randomly allocated to placebo, 100 or 200 mg modafinil and 3 h later completed 100 mm visual analogue scales relating to mood and bodily symptoms, before and after an extensive battery of cognitive tests (pen and paper and CANTAB). There were no significant differences between the three treatment groups on any of the cognitive tests used in this study. There was a significant post-treatment change in the factor measuring 'somatic anxiety' and in individual ratings of 'shaking', 'palpitations', 'dizziness', 'restlessness', 'muscular tension', 'physical tiredness' and 'irritability', which was mainly due to significantly higher ratings of somatic anxiety in the 100 mg group compared with the other two groups. Further changes in mood were revealed after the stress of cognitive testing, with the 100 mg group showing greater increases in the 'psychological anxiety' and the 'aggressive mood' factors (as measured from the Bond and Lader scales).
... As yet the present data are the first evidence of cognitive effects of GLY-B site ligands in the ETM inhibitory avoidance task. However, there is evidence in humans showing that the administration of bioglycine, a biologically active analog of glycine, improves the sustained attention and, most markedly, the retrieval of episodic memory (File et al., 1999). Moreover, although there is little evidence that GLY-B site ligands improve the working memory in humans (Barch, 2004 ), the assessment of working memory in animals using the operant delayed match-to-position task showed that the GLY-B site antagonist (þ)-HA-966 reduced the accuracy in this task independent of the delay (Doyle et al., 1998). ...
Rat behaviors in the elevated T-maze (ETM) were evaluated following tectum microinjections of either glycine (GLY, 1, 10, 80 and 120 nmol) or d-serine (D-SER, 160 and 320 nmol), the putative endogenous agonists of GLY-B site at NMDA receptor, or the respective antagonist 7-chloro-kynurenic acid (7CK, 8 nmol). ETM performance was appraised by two validated scores of anxiety, i.e., the inhibitory avoidance duration (AD) and risk assessment behavior, and two scores derived from a newly developed approach to inhibitory avoidance learning curves, i.e., the learning median number of trials (T50) and avoidance variability (standard deviation of learning curve). Effects on aversive memory consolidation were assessed through changes in the AD measured 48 h after the full-acquisition of inhibitory avoidance. Drug effects were compared to those of vehicle. In most cases, microinjection of GLY-B site agonists into the dorsal periaqueductal gray (dPAG) produced increases in AD, which were compatible with an increase in anxiety. However, neither the intra-periaqueductal injection of 80 nmol GLY, nor that of 160 nmol D-SER, increased the AD. On the other hand, these microinjections invariably produced a parallel left shift in avoidance learning curves, thereby reducing the T50 but not the variability. Effects of 120 nmol GLY on AD and T50 were both antagonized by a previous microinjection of 7CK into the dPAG. The inverse relationship of AD and T50 suggests that increases in the anxiety level reduce the number of trials required for the acquisition of inhibitory avoidance. The above data also suggest the higher consistency and drug sensitivity of T50 as compared to the AD. In turn, whereas the microinjection of 120 nmol GLY into the superior colliculus (SC) did not affect the T50, it increased the AD. On the other hand, there was an increase in avoidance variability following the microinjection of either 120 nmol GLY into the SC or 8 nmol 7CK into the dPAG. Therefore, the GLY-B receptors within these structures seem to play opposite roles on avoidance variability. In contrast, neither of these treatments changed T50. Finally, whereas the risk assessment was solely decreased by the microinjection of GLY into the SC, the aversive memory was only impaired by the microinjection of 7CK into the dPAG. Overall, these data suggest that NMDA/GLY-B receptors of dPAG mediate both anxiety and aversive memory, while those in the SC are most likely involved with attention and visuomotor components of risk assessment behavior.
The restriction of calories, branched-chain amino acids, and methionine have all been shown to extend lifespan in model organisms. Recently, glycine was shown to significantly boost longevity in genetically heterogenous mice. This simple amino acid similarly extends lifespan in rats and improves health in mammalian models of age-related disease. While compelling data indicate that glycine is a pro-longevity molecule, divergent mechanisms may underlie its effects on aging. Glycine is abundant in collagen, a building block for glutathione, a precursor to creatine, and an acceptor for the enzyme Glycine N-methyltransferase (GNMT). A review of the literature strongly implicates GNMT, which clears methionine from the body by taking a methyl group from S-adenosyl-L-methionine and methylating glycine to form sarcosine. In flies, Gnmt is required for reduced insulin/insulin-like growth factor 1 signaling and caloric restriction to fully extend lifespan. The geroprotector spermidine requires Gnmt to upregulate autophagy genes and boost longevity. Moreover, the overexpression of Gnmt is sufficient to extend lifespan and reduce methionine levels. Sarcosine, or methylglycine, declines with age in multiple species and is capable of inducing autophagy both in vitro and in vivo. Taken all together, existing evidence suggests that glycine prolongs life by mimicking methionine restriction and activating autophagy.
Celem obecnych rozważań jest spojrzenie na problem udoskonalania człowieka, a zwłaszcza jego cech psychicznych, z perspektywy nauk biologicznych. Wprowadzono więc używane w biologii rozróżnienie genotypu i fenotypu, definicje cech dziedzicznych i nabytych oraz antropologiczną charakterystykę gatunku Homo sapiens przez cechy specyficznie ludzkie. Perspektywa biologiczna (a zwłaszcza ewolucyjna) wskazuje na ogromne trudności w określeniu charakteru i zakresu możliwych ulepszeń naszego gatunku, co związane jest między innymi z problematyką normy biologicznej oraz psychicznej. Wiele uwagi poświęcono złożonym zależnościom między genotypem i fenotypem w żywych organizmach, wyrażającym się m.in. przez polimorfizm oraz efekty epigenetyczne, a także związkom między genami i cechami psychicznymi człowieka. Ostatecznie stwierdzono, że udoskonalanie np. zdolności poznawczych wymaga pełnego zrozumienia tych związków i zależności, uwzględniającego także różnice indywidualne, które wciąż jest jednak dla nas nieosiągalne.
Celem obecnych rozważań jest spojrzenie na problem udoskonalania człowieka, a zwłaszcza jego cech psychicznych, z perspektywy nauk biologicznych. Wprowadzono więc używane w biologii rozróżnienie genotypu i fenotypu, definicje cech dziedzicznych i nabytych oraz antropologiczną charakterystykę gatunku Homo sapiens przez cechy specyficznie ludzkie. Perspektywa biologiczna (a zwłaszcza ewolucyjna) wskazuje na ogromne trudności w określeniu charakteru i zakresu możliwych ulepszeń naszego gatunku, co związane jest między innymi z problematyką normy biologicznej oraz psychicznej. Wiele uwagi poświęcono złożonym zależnościom między genotypem i fenotypem w żywych organizmach, wyrażającym się m.in. przez polimorfizm oraz efekty epigenetyczne, a także związkom między genami i cechami psychicznymi człowieka. Ostatecznie stwierdzono, że udoskonalanie np. zdolności poznawczych wymaga pełnego zrozumienia tych związków i zależności, uwzględniającego także różnice indywidualne, które wciąż jest jednak dla nas nieosiągalne.
Protective effects of vitamin E (Vit E) on long term potentiation (LTP) impairment, neuronal apoptosis and increase of nitric oxide (NO) metabolites in the hippocampus of juvenile rats were examined. The rats were grouped (n=13) as: (1) control; (2) hypothyroid (Hypo) and (3) Hypo-Vit E. Propylthiouracil (PTU) was given in drinking water (0.05%) during 6 weeks. Vit E (20 mg/ kg) was daily injected (IP). To evaluate synaptic plasticity, LTP from the CA1 area of the hippocampus followed by high frequency stimulation to the ipsilateral Schafer collateral pathway was carried out. The cortical and hippocampal tissues were then removed to measure NO metabolites. The brains of 5 animals in each group were removed for apoptosis study. The hypothyroidism status decreased the slope, 10-90% slope and amplitude of field excitatory post synaptic potential (fEPSP) compared to the control group (P<0.01-P<0.001). Injection of Vit E increased the slope, 10-90% slope and amplitude of the fEPSP in the Hypo-Vit E group in comparison to the Hypo group (P<0.05-P<0.01). TUNEL positive neurons and NO metabolites were higher in the hippocampus of the Hypo rats, as compared to those in the hippocampus of the control ones (P<0.001). Treatment of the Hypo rats by Vit E decreased apoptotic neurons (P<0.01-P<0.001) and NO metabolites (P<0.001) in the hippocampus compared to the Hypo rats. The results of the present study showed that Vit E prevented the LTP impairment and neuronal apoptosis in the hippocampus of juvenile hypothyroid rats.
Memory manipulation has advanced substantially in recent years to a range of new methods available to researchers. These methods include optogenetics, transcranial stimulation, deep brain stimulation, pharmacological agents and cued reactivation of memories during sleep. Here we review and evaluate findings from these methods in relation to manipulations of hippocampus-dependent memories. In doing so we shed light on the different ways in which memories can be erased, enhanced or implanted.
Currently, several types of amino acids are being produced and used worldwide. Nevertheless, several new functions of amino acids have been recently discovered that could result in other applications. For example, oral stimulation by glutamate triggers the cephalic phase response to prepare for food digestion. Further, the stomach and intestines have specific glutamate-recognizing systems in their epithelial mucosa. Regarding clinical applications, addition of monosodium glutamate to the medicinal diet has been shown to markedly enhance gastric secretion in a vagus-dependent manner. Branched-chain amino acids (BCAAs) are the major components of muscles, and ingestion of BCAAs has been found to be effective for decreasing muscle pain. BCAAs are expected to be a solution for the serious issue of aging. Further, ingestion of specific amino acids could be beneficial. Glycine can be ingested for good night's sleep: glycine ingestion before bedtime significantly improved subjective sleep quality. Ingestion of alanine and glutamine effectively accelerates alcohol metabolism, and ingestion of cystine and theanine effectively prevents colds. Finally, amino acids could be used in a novel clinical diagnostic method: the balance of amino acids in the blood could be an indicator of the risk of diseases such as cancer. These newly discovered functions of amino acids are expected to contribute to the resolution of various issues.
The development of drugs for the treatment of disorders of cognition has benefited from a more precise knowledge of the loss of specific neural pathways associated with certain neurodegenerative diseases such as Alzheimer's disease (AD). The loss of basal forebrain cholinergic neurons in AD has engendered the development of new compounds that target various aspects of the cholinergic system. However, limitations in the effectiveness of the most common of these, the anticholinesterases, have fueled the race to provide more efficacious compounds. In an attempt to avoid side effects and improve efficacy, other neuronal targets have been considered, including receptors for norepinephrine, dopamine, serotonin, excitatory amino acids, neural peptides, and others. Our laboratory has had the opportunity to study the memory-enhancing potential of many of the compounds developed expressly for these neuronal targets in macaques. Upon reviewing 21 such studies it was evident that: 1) To varying degrees, pharmacological manipulation of each target yielded improved task performance. 2) Combining pharmacological targets could lead to additive or synergistic effects on task performance. 3) Mature adult and aged monkeys provided equivalent estimates of drug effectiveness. 4) There appeared to be no limiting level of task improvement for compounds tested in aged and younger monkeys. 5) Certain of these agents also exhibited potential disease-modifying actions. Thus, certain memory-enhancing agents may prove more useful when implemented early in the course of a disease such as AD, and they also may enjoy a wide application for the treatment of the memory decline associated with normal aging.
The conformational behavior and vibrational spectra of cyclo(Gly-Leu) dipeptide, which is an important biological active compound and a therapeudic agent, have been investigated by computational methods. The theoretically possible stable conformers of free cyclo(Gly-Leu) dipeptide in electronic ground state were obtained by performing conformational analysis following DFT calculations. Further, to predict the intermolecular hydrogen bonding interactions in solid phase, various dimer structures were modeled. The optimized geometry and the wavenumbers for cyclo(Gly-Leu) and its dimers have been calculated by DFT method with B3LYP functional, 6–31 + +G(d,p) basis set. The complete assignment of the bands was performed based on the potential energy distributions (PED%) and experimental wavenumber shifts upon N- deuteration. General agreements between the observed and calculated frequencies are shown. Chemical interpretation of hyperconjugative interactions was carried out by natural bond orbital (NBO) analysis. Finally, HOMO and LUMO energy levels have been calculated.
Lead (Pb) exposure during development is associated with impaired cognitive function and long-term potentiation (LTP). Vitamin E (VE) is an antioxidant that could have protective effects against Pb intoxication. In this study, we examined the protective effects of vitamin E against Pb-induced LTP impairments. Forty-six adult male Wistar rats were randomly divided into 6 treatment groups: (1) control; (2) Pb exposure; (3) VE; (4) Pb +VE; (5) Pb exposure followed by VE 2 months after exposure; (6) VE followed by Pb exposure 1 month after treatment. Rats were exposed to Pb through daily consumption of Pb-contaminated distilled water; VE was administered by daily gavage for 3 months. After this period, the population spike (PS) amplitudes and the slopes of excitatory postsynaptic potentials (EPSPs) were measured in the dentate gyrus (DG) area of the hippocampus in adult rats in response to electrical stimulation applied to the perforant pathway in vivo. Blood samples were also collected to evaluate malondialdehyde (MDA) levels, total antioxidant capacity (TAC), and total oxidant status (TOS). Biochemical analyses demonstrated significant increases in plasma MDA and TOS levels in the Pb-exposed group compared to the control group. VE-protected groups revealed significant increases in TAC levels. Our results demonstrate that Pb decreased EPSP slopes and PS amplitudes compared to the control group, whereas VE increased these parameters compared to the control group. Co-administration of VE with Pb exposure inhibited Pb-induced effects. These findings suggest that VE via its antioxidant activity reverses Pb-induced impairments of synaptic plasticity in the DG.
Discover effective, outcome-oriented ways to help CFS patients who have endured useless or inappropriate treatments! From the author: "For many years I have viewed brain function as a system of electrochemical impulses continually flashing through the brain. These neural networks can often be modulated fairly simply by 'tuning' them. The point I have been trying to make for many years is that this process may be pharmacologically regulated extremely rapidly in a manner which does not yet seem to be recognized by the medical profession." In this remarkable volume, Dr. Jay A. Goldstein clearly presents both the theoretical and the practical aspects of his revolutionary approach to treating CFS and other conditions that have often been termed psychosomatic. Dr. Goldstein (author of Chronic Fatigue Syndromes: The Limbic Hypothesis and Betrayal by the Brain: The Neurologic Basis of Chronic Fatigue Syndrome, Fibromyalgia Syndrome, and Related Neural Network Disorders) shows how he achieves results for patients with CFS and a variety of other syndromes in days, rather than months or years. This well-referenced book answers questions, from the most basic to the most complex, including: • What is neurosomatic medicine? • How did Dr. Goldstein come to pioneer and practice this specialty? • What abnormalities in brain function produce neurosomatic disorders? • How can an understanding of these abnormalities help you provide effective treatment? • Why do these treatments sometimes work so rapidly? • What is receptor profiling, and how does it indicate the type of receptor dysregulation in an individual patient? In Part I: Inventing Neurosomatic Medicine, Dr. Goldstein describes the remarkable how and why of his life and his development of this new field of medicine, including his clashes with the medical/psychoanalytic establishment. One of the greatest medical innovators of the modern era, Dr. Goldstein has seen over 20,000 CFS patients and has experienced most of the pitfalls that having such a large number of patients entails. He shares his insight on legal issues, such as how to deal with the law and court systems, how to best provide expert testimony, and how to defend against spurious legal actions. In addition, Dr. Goldstein describes how he learned to work effectively outside of the managed care system. In Part II: Society for Neuroscience Conference Proceedings, the author shares his expertise to bring you experimental results and "pearls of wisdom" relating to neurosomatic medicine from the 28th anD 29th Annual Meetings of the Society for Neuroscience-the largest and most important neuroscience conference in the world. Dr. Goldstein sorted through thousands of experiments presented at the conferences to bring you the most relevant findings. Part III: Pathophysiology and Treatment is essential reading for anyone planning to practice neurosomatic medicine. In this section, richly illustrated with over 70 pages of color figures and diagrams that make complicated concepts clear, Dr. Goldstein shares his knowledge about dozens of the agents he uses to help CFS sufferers and others manage their pain, fatigue, and other symptoms. This is information that simply cannot be found anywhere else, and will prove invaluable to all fledgling neurosomatic practitioners. This one-of-a-kind volume is thoughtfully put together-from the extensive list of abbreviations near the beginning to the exhaustive references and an appendix with diagnostic criteria, a treatment algorithm, a medication list of treatment options available now or in the near future, and a checklist of CFS symptoms.
Current research is likely to bring indepth understanding of the mechanisms that underlie cognition, including learning, memory, and selective forgetting. The effects of neurodegeneration and other disease states may differ overall from those in normal aging but there may be an impact on similar processes. Diagnosis of disease states such as dementia is likely to become more accurate and be possible earlier in the disease course. A greater range of options is likely to be available for modifying the course of cognition-impairing disorders and probably for age-related changes. Less likely but possible are agents with large cognition-enhancing effects for use by all age groups beyond therapy. Targeting of treatments and prediction of individual responses might become possible, at least in some scenarios. More research is needed to ensure that disease-modifying drugs are used to maximize benefits and minimize harms, including research on markers to guide treatment choice. The future of cognition enhancers in healthy people is uncertain but diversion and off-label use seems likely to increase. Thus, mechanisms to license or otherwise regulate cognition enhancers marketed at healthy individuals are likely to be considered.
Lead (Pb) is a neurotoxic metal that is widely distributed in the environment. In experimental animals, chronic exposure to this neurotoxicant resulted in impaired synaptic plasticity and cognitive function. In this study, we examined the protective effects of vitamin C (ascorbic acid) against Pb exposure-induced impairment of long-term potentiation (LTP). Forty-four adult male Wistar rats were divided into six groups and subjected to the following treatments for three months: (1) vehicle (distilled water); (2) Pb; (3) ascorbic acid; (4) Pb+ascorbic acid; (5) Pb (two months) followed by ascorbic acid; and (6) ascorbic acid (one month) followed by Pb. After treatment, the population spike(PS) amplitude and slope of excitatory postsynaptic potentials(EPSP) were measured in the dentate gyrus(DG) of rats in vivo. Following these measurements, blood samples were collected for the following biochemical assays: malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidant status (TOS). There was a significant increase in plasma MDA and TOS in the Pb-intoxicated group compared to the control group. There was a significant increase in TAC levels in the ascorbic acid group. Our results also show that Pb exposure caused a decrease in the EPSP slope and PS amplitude when compared with the control group, whereas vitamin C increased these parameters. Co-administration of Pb with vitamin C inhibited the effects of Pb. These findings suggested that Pb exposure caused impairment in LTP, that may have been mediated through oxidative damage. Vitamin C ameliorated the Pb-induced impairment of synaptic plasticity in the DG via antioxidant activity.
Copyright © 2015. Published by Elsevier Inc.
The efficacy of compounds having agonistic activity at the glycine site associated with the N-methyl-D-aspartate receptor (NMDAR) is presently assessed in psychiatric disorders. In contrast to NMDAR antagonists, the neuropsychiatric effects of NMDAR agonists in the healthy human organism are not known. We studied neuropsychiatric and neurochemical effects of the NMDAR-glycine site obligatory co-agonist D-serine (DSR) in healthy subjects using a randomized, controlled crossover challenge design including a baseline assessment day and two DSR/placebo administration days. Thirty-five subjects aged 23-29 years participated in the study and received a 2.1g orally administered DSR dose. The main outcome measures were the changes in scores of mood-related Visual Analogue Scale (VAS), Continuous Performance Test–Identical Pairs (CPT-IP), and Rey Auditory Verbal Learning Test (RAVLT). DSR acute administration: (1) was well tolerated and resulted at 2 hours in ≥200 times increase in DSR serum levels; (2) elicited reduced VAS-measured depression and anxiety feelings; (3) improved attention and vigilance as measured by CPT-IP d-prime score; (4) preferentially improved performance in RAVLT list 7 reflecting ability to retain information over interference; (5) had significant but nonspecific effects on Category Fluency and Benton Visual Retention tests; and (6) did not affect glycine and glutamate serum levels. These data indicate that in healthy subjects, DSR reduces subjective feelings of sadness and anxiety and has procognitive effects that are overall opposed to the known effects of NMDAR antagonists. The findings are relevant to translational research of NMDAR function and the development of NMDAR-glycine site treatments for specific psychiatric entities.
Cognitive impairment is integral to many neurological illnesses. Specific enhancement of glutamatergic transmission may improve memory and learning. Org 25935 increases the synaptic availability of glycine, an obligate co-agonist with glutamate at N-methyl-D-aspartate receptors. We hypothesised that Org 25935 would acutely improve the learning and memory of healthy volunteers.
A randomised, double-blind, parallel-group, single-dose study of Org 25935 and placebo was carried out. Thirty-two healthy male volunteers took either 12-mg Org 25935 or matching placebo and were later assessed with the manikin task, digit span and verbal memory tests. Systematic assessments of cardiovascular and adverse events were also taken.
There was no effect of Org 25935 on reaction time, number of correct responses or learning (greater or slower improvement over successive tasks) compared with placebo. Org 25935 caused significantly more dizziness and drowsiness compared with placebo; these side effects were mainly mild.
A single dose of Org 25935 does not improve learning or memory in healthy male individuals. However, the drug was well tolerated, and it remains to be seen whether it would have a positive effect on cognition in patient groups with pre-existing cognitive deficits. Copyright © 2014 John Wiley & Sons, Ltd.
Silk fibroins are biomaterials that have been applied to surgical sutures, drug delivery systems, food supplements, and tissue engineering. Studies have shown the antiadipogenic effects of silk proteins in 3T3-L1 cells and obese mice. Furthermore, other studies have shown that silk proteins increase osteogenic marker expression in osteoblast-like cells. Because osteogenic and adipogenic differentiation from common mesenchymal progenitor cells are often regulated reciprocally, we hypothesized that silk proteins would stimulate osteoblast differentiation. The objective of this study was to evaluate the effects of silk proteins on promoting osteoblast differentiation and identify the underlying mechanism. We showed that silk proteins dose dependently stimulated alkaline phosphatase (ALP) activity, osteoblast differentiation, and induced expression of osteoblast markers in C3H10T1/2 and M2-10B4 multipotent cells. In addition, silk proteins also induced the expression of osteoblast markers in primary rat bone marrow cells isolated from tibiae. Molecular studies showed that silk proteins suppressed the expression of Notch-activated genes and blocked activation of the Notch-specific reporter. Similarly, inhibiting Notch signaling with pharmacologic inhibitors and by small interfering RNA-mediated Notch1 silencing also induced ALP activity and messenger RNA expression. Finally, induction of ALP activity and messenger RNA expression by silk proteins was blunted in Notch1 knock-downed cells, further demonstrating Notch signaling as an important mediator for the pro-osteogenic effects of silk proteins. Taken together, our data suggest that silk proteins may serve as functional foods to promote bone healing and therapeutic interventions for bone fractures and osteoporosis.
Glutamatergic system – main excitatory brain system is involved in pathophysiology of schizophrenia. Ionotropic glutamatergic NMDA receptor plays an important role in cognitive functioning and participates in mechanisms of control of dopaminergic, noradrenergic and serotoninergic systems. NMDA receptor antagonists as phencyclidyne or ketamine can induce psychosis similar to schizophrenia including also negative and cognitive symptomatology. Glycine is a natural coagonist of NMDA receptor necessary to its proper functioning. Treatment with high doses of glycine (max. 60g orally per day) according to hypothesis of decreased NMDA receptor activity can improve negative symptoms and cognitive functions in schizophrenia.
Purpose of the study: The aim of study was evaluation of changes in cognitive functioning of schizophrenic patients in stable mental state, with predominant negative symptoms (mean 25.7 points in PANSS-Negative symptom subscale), before and after 6-weeks augmentation of antipsychotic treatment with glycine.
Methods: 29 patients with diagnosis of schizophrenia (ICD-10 criterias) in stable clinical state had completed 6 weeks, prospective, open label study (32 patients were enrolled). Patients were treated with antipsychotics (typical and second generation neuroleptics) in stable dosage for at least 3 months. Before and afterwards glycine treatment (0,8 g/kg/day) cognitive functions were assessed with battery of standard neuropsychological tests: Wisconsin Card Sorting Test (WCST, version for PC), Trail Making Test (TMT) and Stroop Task. Clinical changes in negative symptoms were also assessed using PANSS-Negative symptom subscale.
Results: Improvement of working memory, attention and verbal functions after glycine treatment was significant in our group. In week 6 patients used less cards to finish more categories (p<0,001), making significantly fewer perseverative (p<0,001) and nonperseverative (p<0,01) errors. Afterwards glycine intake time needed to finish both parts of TMT was shorter (p<0,01). There was a significant decrease of numbers of errors and period of time necessary to finish second part of Stroop test, what indicates better verbal functioning and attention. Significant improvement in negative symptoms (PANSS-Negative symptom subscale; -16,1%; p<0,001) after use of glycine were observed.
Conclusions: Augmentation of antipsychotic treatment with glycine can improve cognitive functions and negative symptoms in schizophrenic patients. Combined medication was safe and well tolerated. Some patients complained on nausea or gastric discomfort.
The effects of glycine on sleep quality were examined in a randomized double-blinded cross-over trial. The volunteers, with complaints about the quality of their sleep, ingested either glycine (3 g) or placebo before bedtime, and their subjective feeling in the following morning was evaluated with the St. Mary's Hospital Sleep Questionnaire and Space-Aeromedicine Fatigue Checklist. The glycine ingestion significantly improved the following elements: “fatigue”, “liveliness and peppiness”, and “clear-headedness”. These results suggest that glycine produced a good subjective feeling after awakening from sleep.
This chapter contains section titled: Summary The decline of cognitive function with aging From benign senescent forgetfulness to age-associated cognitive decline Problems with AAMI and AACD Study selection Types of compound used Outcomes assessed Results Discussion and conclusions Summary The decline of cognitive function with aging From benign senescent forgetfulness to age-associated cognitive decline Problems with AAMI and AACD Study selection Types of compound used Outcomes assessed Results Discussion and conclusions
The theoretical conformational analysis of cyclic dipeptide, cyclo(glycine–valine), which has anticancer activity, has been performed by molecular mechanics method, in order to examine the energetically optimal conformational states. The relative positions of the side chain residues of the stable conformations of dipeptide were obtained. The obtained geometry of the most stable conformation of the cyclo(Gly–Val) was optimized using DFT method at B3LYP/6-31++G(d,p) level of theory. Afterwards dimeric forms of the dipeptide were formed and energetically preferred conformations of dimers were investigated using the same method and the same level of theory. The experimental IR and micro-Raman spectra of solid cyclo(Gly–Val) were reported for the first time. The vibrational normal modes and associated wavenumbers, IR intensities and Raman activities of the monomeric and dimeric forms of the dipeptide were calculated using DFT method at B3LYP/6-31++G(d,p) level of theory and the results were compared with the experimental data. The total energy distributions (TED) of the vibrational modes were calculated by using Scaled Quantum Mechanical (SQM) analysis. Vibrational assignment was performed on the basis of calculated total energy distribution (TED) of the modes.
Glycine strongly reduces the serum levels of pro-inflammatory cytokines and increases the levels of anti-inflammatory cytokines. Recently, glycine has been shown to decrease the expression and secretion of pro-inflammatory adipokines in monosodium glutamate-induced obese (MSG/Ob) mice. It has been postulated that these effects may be explained by a reduction in nuclear factor kappa B (NF-κB) activation. NF-κB is a transcription factor, which is crucial to the inflammatory response. Hasegawa et al. (2011 and 2012) recently reported a glycine-dependent reduction in NF-κB levels. Here, we have investigated the role of glycine in the regulation of NF-κB in differentiated 3T3-L1 adipocytes. The results revealed that pretreatment with glycine interfered with the activation of NF-κB, which has been shown to be stimulated by tumor necrosis factor-alpha (TNF-α). Glycine alone stimulated NF-κB activation in an unusual way such that the inhibitor κB-β (IκB-β) degradation was more significant than that of the inhibitor κB-α (IκB-α) and led to NF-κB complexes comprised of p50 and p65 subunits; IκB-ε degradation did not affect by glycine. These findings suggest that glycine could be used as an alternative treatment for chronic inflammation, which is a hallmark of obesity and other comorbidities, and is characterized by an elevated production of pro-inflammatory cytokines.
Cognition denotes a relatively high level of processing of specific information including thinking, memory, perception, motivation, skilled movements and language. Cognitive psychology has become an important discipline in the research of a number of psychiatric disorders, ranging from severe psychotic illness such as schizophrenia to relatively benign, yet significantly disabling, non-psychotic illnesses such as somatoform disorder. Research in the area of neurocognition has started unlocking various secrets of psychiatric disorders, such as revealing the biological underpinnings, explaining the underlying psychopathology and issues related to course, outcome and treatment strategies. Such research has also attempted to uproot a number of previously held concepts, such as Kraepelin's dichotomy. Although the range of cognitive problems can be diverse, there are several cognitive domains, including executive function, attention and information processing, and working memory, which appear more frequently at risk. A broad range of impairment across and within the psychiatric disorders are highlighted in this oration. The oration summarizes the studies investigating cognitive processing in different psychiatric disorders. I will also discuss the findings of my own research on neurocognitive deficits in mood disorders, schizophrenia, obsessive-compulsive disorder, somatoform disorder, including studies on 'high-risk' individuals. Tracing the evaluation of neurocognitive science may provide new insights into the pathophysiology and treatment of psychiatric disorders.
Glycine is a classical inhibitory neurotransmitter however presynaptic glycine receptors have rather depolarizing action. Reasons for latter phenomenon are unknown. In the present paper we have investigated how glycine influences cytosolic chloride level monitored by fluorescent dye SPQ, membrane potential monitored by fluorescent dye DiSC3(5) and [(14)C]-glutamate release in synaptosomes. We estimated that cytosolic chloride concentration in synaptosomes was about 52 +/- 1 mM. Glycine (1 mM) induced chloride efflux and caused slow plasma membrane depolarization. Chloride efflux was almost completely blocked by 100 microM strychnine whilst glycine-induced depolarization was only partially. We also showed that 1 mM glycine induced [(14)C]-glutamate release via a strychnine-insensitive pathway. Hence we have concluded that glycine was able to induce two independent effects in synaptosomes: (1) Chloride efflux with following depolarization. This efflux was sensitive to strychnine and thereby is probably conducted through glycine-gated ion channels. (2) Glutamate release seems to be mediated by glycine transporters.
Natural fragmentation of peptide and other chemical structures is well known. They are a significant object of biochemical investigations. In this connection, the bases and determination are given for the notion of the "fragmentome" as a set of all fragments of a single substance, as well as for global fragmentome of all chemical components of living organisms. It is described how protein-peptide fragments are formed in nature, what experimental and theoretical methods are used for their investigation, as well as mathematical characteristics of fragmentomes. Individual fragmentomes of all subunits and of complete casein fragmentome are considered in detail. Structural and functional variety of its possible fragments was revealed by computer analysis. Formation in an organism of an exogenous-endogenous pool of oligopeptides and correlation of these data with concepts of structure-functional continuum of regulatory molecules is shown on an example of food protein fragments. Possible practical importance of the use of natural fragments in dietology, therapy, as well as in sanitary hygiene and cosmetics is noted.
Soya foods are rich in isoflavone phytoestrogens with weak agonist activity at oestrogen receptors. Oestrogen treatment has been found to improve memory in men awaiting gender reassignment and in post-menopausal women.
To examine the effects of supervised high versus low soya diets on attention, memory and frontal lobe function in young healthy adults of both sexes.
Student volunteers were randomly allocated to receive, under supervision, a high soya (100 mg total isoflavones/day) or a low soya (0.5 mg total isoflavones/day) diet for 10 weeks. They received a battery of cognitive tests at baseline and then after 10 weeks of diet.
Those receiving the high soya diet showed significant improvements in short-term (immediate recall of prose and 4-s delayed matching to sample of patterns) and long-term memory (picture recall after 20 min) and in mental flexibility (rule shifting and reversal). These improvements were found in males and females. In a letter fluency test and in a test of planning (Stockings of Cambridge), the high soya diet improved performance only in females. There was no effect of diet on tests of attention or in a category generation task. Those on the high soya diet rated themselves as more restrained and, after the tests of memory and attention, they became less tense than did those on the control diet.
Significant cognitive improvements can arise from a relatively brief dietary intervention, and the improvements from a high soya diet are not restricted to women or to verbal tasks.
In an open study, self-ratings of bodily symptoms, mood (before and after stress), and cognitive performance were investigated in 25 women (aged 54-66 years) who for approximately 10 years had been taking an oral preparation of hormone replacement therapy (HRT), tibolone (Livial; 2.5 mg/ day). Tibolone has a unique profile, with estrogenic, progestogenic, and androgenic actions. The control group of 25 women had never taken HRT. Each woman in this group was pair-matched to one in the tibolone group on age, years since menopause, IQ, years of secondary education, and occupation. The groups were matched on their anxiety and depression scores on the Hospital Anxiety and Depression rating scale. Exclusion criteria were scores on this scale in the clinical range and any current illness or recent use of psychoactive medication. The women who were taking tibolone felt significantly less clumsy and had less severe palpitations than the control group. After exposure to a mildly stressful test, the control group felt more anxious, but this change was not seen in the group receiving tibolone. The group taking tibolone had significantly better semantic memory (memory for facts), as assessed in a category generation task, but they did not differ in tests of episodic memory (memory for events). An unexpected finding was that the tibolone group performed significantly worse on a sustained attention task and a planning task, tasks that are associated with frontal lobe function. Our results suggest that the effects of HRT on cognition may be influenced by the type of HRT, the duration of treatment, the nature of the tests, and the brain region controlling the cognitive function.
In an open study, we determined whether there were sex differences in the mood ratings of non-deprived light smokers and nonsmokers under baseline conditions and after completing a battery of cognitive tests that were mildly stressful. Male and female students who were light smokers (5-12 cigarettes a day) were tested immediately after smoking their usual cigarette, at a time that they normally smoked. They were compared with a group of male and female students who were nonsmokers and did not differ on age, IQ, personality measures, anxiety or depression. Compared with the nonsmokers, both male and female smokers felt overall significantly more discontented, troubled, tense, quarrelsome, furious, impatient, hostile, annoyed and disgusted and experienced greater dizziness. The performance of distracting cognitive tasks did not reveal anxiolytic effects of smoking, and after performance of these tasks, both smokers and nonsmokers became more discontented and anxious. In addition, after the cognitive testing, both male and female smokers showed greater increases than nonsmokers in feeling spiteful, rebellious, incompetent and in sweating, suggesting that they experienced greater mood changes in response to cognitive stress. There were no overall differences between the smokers and nonsmokers in the performance of divided or sustained attention tasks or in episodic memory. It is unlikely that either nicotine withdrawal or differences in cognitive performance could account for the greater anxiety, discontent and aggressive mood that was found in smokers.
We previously reported that a high soya diet improved memory and frontal lobe function in young volunteers, and since soya isoflavones are agonists at oestrogen receptors, they may improve these functions in postmenopausal women. Thirty-three postmenopausal women (50-65 years) not receiving conventional hormone replacement therapy (HRT) were randomly allocated in a double-blind parallel study to receive a soya supplement (60 mg total isoflavone equivalents/day) or placebo for 12 weeks. They received a battery of cognitive tests and completed analogue rating scales of mood and sleepiness, and a menopausal symptoms questionnaire before the start of treatment and then after 12 weeks of treatment. Those receiving the isoflavone supplement showed significantly greater improvements in recall of pictures and in a sustained attention task. The groups did not differ in their ability to learn rules, but the isoflavone supplement group showed significantly greater improvements in learning rule reversals. They also showed significantly greater improvement in a planning task. There was no effect of treatment on menopausal symptoms, self-ratings of mood, bodily symptoms or sleepiness. Thus, significant cognitive improvements in postmenopausal women can be gained from 12 weeks of consumption of a supplement containing soya isoflavones that are independent of any changes in menopausal symptoms, mood or sleepiness.
Research on the cognitive and brain structural correlates of schizophrenia has seen tremendous progress over the past decade. It has become increasingly clear that there is no pathognomic neuropsychological or structural neuroanatomic profile in schizophrenia, likely due in part to etiological heterogeneity within the disorder. Nonetheless, several studies have indicated that verbal episodic memory and vigilance deficits are particularly prominent, and are observed even in untreated patients in their first episode of the disorder. The course of schizophrenia appears to be somewhat variable, and factors that contribute to the development of the illness, and in some patients, deterioration of cognitive functioning, have not been elucidated clearly. Neurodevelopmental factors, however, likely play an important role in the diathesis of the disorder, while neuropathological processes contribute to deterioration and progression. At this time, there are relatively few controlled comparisons of the cognitive effects of atypical and conventional antipsychotic medications. Additional studies of the potential effects of antipsychotic medications on structural brain abnormalities are warranted. It is hoped that newer innovative psychopharmacological approaches and neuropsychological remediation programs will, in the not-too-distant future, provide clinicians with a variety of means to improve the cognitive and social functioning of their patients.
Men and women (50-67 years) completed drinking diaries and, on the basis of this, were divided into low (<2 units/day, 1 UK unit=8 g alcohol) and moderate (2-5 units/day) alcohol groups. They completed analogue rating scales of mood and bodily symptoms before and after two extended computerised cognitive tests. After the tests, the women showed significantly greater increases in self-ratings on the factors of anxiety and discontentment and felt significantly less alert than did the men. They also showed significantly greater increases in bodily symptoms of somatic anxiety and ratings of aggressive mood than did the men. There were no significant effects of alcohol or Sex x Alcohol interactions on the self-ratings, but the men showed significant positive correlations of alcohol and negative mood. On both the cognitive tests, there were significant Sex x Alcohol interactions because the moderate-drinking men performed worse than the low-drinking men, whereas the moderate-drinking women performed better than the low-drinking women. Thus, the middle-aged women responded much more than did the men with negative mood changes to the psychological stress of cognitive testing, although their cognitive performance was not worse.
The adsorption of amino acids (AA) (glycine, L-alanine, L-proline) on oxidized cellulose (OC) with various carboxyl contents and degrees of crystallinity from aqueous and water/ethanol solutions was studied. It was found that multilayer adsorption occurs in concentrated solutions of AA. It proceeds according to successive mechanisms via adsorption of AA zwitterions onto carboxyls of already adsorbed AA. This leads to formation of chain AA associates in the OC phase. A sharp increase in swelling accompanies multilayer adsorption. It was established that structural characteristics and degree of polymerization of OC are the main factors that affect multilayer adsorption. The distribution of carboxyls in the OC phase also plays an important role. Multilayer adsorption does not proceed in water/ethanol solutions and in the case of the cationic form of AA.
This study compared 32 patients with ischemic vascular dementia (IVD) to 32 patients with probable Alzheimer's disease (AD) on select language and verbal memory tests. The IVD and AD patients were individually matched on the basis of age, dementia severity, years of education, and gender. The IVD patients had poorer verbal fluency, but better free recall, fewer recall intrusions, and better recognition memory than the AD patients. Relationships between the neuropsychological measures and radiological indexes of cortical and subcortical pathology were also examined. A number of infarcts, white-matter lucency, and ventricular enlargement correlated with some of the neuropsychological measures; cortical atrophy correlated with most of the measures. The findings suggest that neuropsychological deficits in IVD may be related to dysfunction of frontal-subcortical circuits, although an associated degenerative cortical process may also be involved.
Effortful and automatic memory task performances were examined in 36 schizophrenic patients and 18 normal control Ss. Tasks included free recall, recognition, and frequency estimation. Patients demonstrated impairment in recall, in recognition, in semantic encoding, and in frequency estimation. Deficits were observed across tasks despite differences in attentional demands. The results suggest a basic compromise of memory function, which is consistent with recent neuroimaging evidence of structural or physiological abnormalities in frontal and temporal lobe structures in schizophrenia.
Patients with Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD), and normal controls were compared on 2 versions of a semantic fluency task: a standard, uncued version and a version in which Ss were cued with subordinate categories. All patients were impaired relative to controls on the standard version. On the cued version, PD and HD patients improved significantly, but AD patients did not. AD patients' fluency, but not PD or HD patients', correlated significantly with confrontation naming ability. Impairment exhibited by PD and HD patients on standard semantic fluency tasks may be due to a retrieval deficit, whereas that of AD patients may be due to degradation of semantic memory stores. In addition, the pattern of performance exhibited by a nonaphasic patient with bilateral frontal lobe lesions suggests that the retrieval functions involved may depend on integrity of the prefrontal cortex. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Caffeine is the most widely consumed centralnervous-system stimulant. Three main mechanisms of action of caffeine on the central nervous system have been described. Mobilization of intracellular calcium and inhibition of specific phosphodiesterases only occur at high non-physiological concentrations of caffeine. The only likely mechanism of action of the methylxanthine is the antagonism at the level of adenosine receptors. Caffeine increases energy metabolism throughout the brain but decreases at the same time cerebral blood flow, inducing a relative brain hypoperfusion. Caffeine activates noradrenaline neurons and seems to affect the local release of dopamine. Many of the alerting effects of caffeine may be related to the action of the methylxanthine on serotonine neurons. The methylxanthine induces dose-response increases in locomotor activity in animals. Its psychostimulant action on man is, however, often subtle and not very easy to detect. The effects of caffeine on learning, memory, performance and coordination are rather related to the methylxanthine action on arousal, vigilance and fatigue. Caffeine exerts obvious effects on anxiety and sleep which vary according to individual sensitivity to the methylxanthine. However, children in general do not appear more sensitive to methylxanthine effects than adults. The central nervous system does not seem to develop a great tolerance to the effects of caffeine although dependence and withdrawal symptoms are reported.
Effortful and automatic memory task performances were examined in 36 schizophrenic patients and 18 normal control Ss. Tasks included free recall, recognition, and frequency estimation. Patients demonstrated impairment in recall, in recognition, in semantic encoding, and in frequency estimation. Deficits were observed across tasks despite differences in attentional demands. The results suggest a basic compromise of memory function, which is consistent with recent neuroimaging evidence of structural or physiological abnormalities in frontal and temporal lobe structures in schizophrenia.
Recent work has shown that the hippocampus contains a class of receptors for the excitatory amino acid glutamate that are activated by N-methyl-D-aspartate (NMDA) and that exhibit a peculiar dependency on membrane voltage in becoming active only on depolarization. Blockade of these sites with the drug aminophosphonovaleric acid (AP5) does not detectably affect synaptic transmission in the hippocampus, but prevents the induction of hippocampal long-term potentiation (LTP) following brief high-frequency stimulation. We now report that chronic intraventricular infusion of D,L-AP5 causes a selective impairment of place learning, which is highly sensitive to hippocampal damage, without affecting visual discrimination learning, which is not. The L-isomer of AP5 did not produce behavioural effects. AP5 treatment also suppressed LTP in vivo. These results suggest that NMDA receptors are involved in spatial learning, and add support to the hypothesis that LTP is involved in some, but not all, forms of learning.
Eight patients with Parkinson's disease and eight matched controls were tested for concurrent task performance to examine whether Parkinson's disease produces deficits in the coordinating and integrating function of the central executive component of Baddeley's working memory model. Consistent with this prediction, the patients showed a significant decline in performance on a random pursuit tracking task while recalling digit span forward sequences, whereas the controls showed no such change. Performance on the component pursuit and digit span tasks, which did not differ between groups, was equated across subjects by varying the size of a target square and by using individual subjects' digit spans. The patient group also produced poorer word fluency scores and reported higher levels of depression, but there was no significant impairment on the Wisconsin card sort test. There was no association between dual task performance and any psychometric measure, target size, or disease related variables. Baddeley's working memory model is advantageous in providing a rich conceptual basis to explore and characterise cognitive abilities in patients with Parkinson's disease.
Synopsis
To examine whether poor verbal fluency in schizophrenia represents a degraded semantic store or inefficient access to a normal semantic store, 25 normal volunteers and 50 DSM-III-R schizophrenic patients, matched for age, sex and IQ, were recruited. Although schizophrenic patients were impaired on both letter and category fluency, they showed a normal pattern of output in that category was superior to letter fluency, and an improvement in category fluency when a cueing technique was employed (Randolph et al. 1993). These results resemble those found in disorders of frontostriatal systems (Parkinson's and Huntington's disease) and suggest that poor verbal fluency in schizophrenia is because of inefficient access to semantic store. A measure of improvement with cueing was directly related to performance on the Stroop executive task. Of all symptom measures derived from SANS and Manchester Scales, only alogia was related to verbal fluency in that superior improvement correlated inversely with the degree of alogia. It is suggested that both alogia and poor verbal fluency are mediated by the same underlying cognitive abnormality that reflects frontostriatal dysfunction.
A theory is proposed to account for some of the age-related differences reported in measures of Type A or fluid cognition. The central hypothesis in the theory is that increased age in adulthood is associated with a decrease in the speed with which many processing operations can be executed and that this reduction in speed leads to impairments in cognitive functioning because of what are termed the limited time mechanism and the simultaneity mechanism. That is, cognitive performance is degraded when processing is slow because relevant operations cannot be successfully executed (limited time) and because the products of early processing may no longer be available when later processing is complete (simultaneity). Several types of evidence, such as the discovery of considerable shared age-related variance across various measures of speed and large attenuation of the age-related influences on cognitive measures after statistical control of measures of speed, are consistent with this theory.
To examine cognitive function in chronic fatigue syndrome.
Twenty patients with chronic fatigue syndrome recruited from primary care and 20 matched normal controls were given CANTAB computerised tests of visuospatial memory, attention, and executive function, and verbal tests of letter and category fluency and word association learning.
Patients with chronic fatigue syndrome were impaired, predominantly in the domain of memory but their pattern of performance was unlike that of patients with amnesic syndrome or dementia. They were normal on tests of spatial pattern recognition memory, simultaneous and delayed matching to sample, and pattern-location association learning. They were impaired on tests of spatial span, spatial working memory, and a selective reminding condition of the pattern-location association learning test. An executive test of planning was normal. In an attentional test, eight subjects with chronic fatigue syndrome were unable to learn a response set; the remainder exhibited no impairment in the executive set shifting phase of the test. Patients with chronic fatigue syndrome were also impaired on verbal tests of unrelated word association learning and letter fluency.
Patients with chronic fatigue syndrome have reduced attentional capacity resulting in impaired performance on effortful tasks requiring planned or self ordered generation of responses from memory.
Estimates of controlled and automatic processes hypothesized to underlie performance in a memory task and in an attention
task were derived for 115 participants from 18 to 78 years of age using the process-dissociation procedure. Participants also
performed speed and neuropsychological tests that were suspected to be negatively related to age. Process estimates showed
good reliability (from .76 to .98), and the qualitative distinction between processes was supported by the overall pattern
of correlations among measures. However, only estimated automatic processes exhibited unique variance, as they were either
weakly related or unrelated both to performance on the other tests and to each other. Estimates of the control processes,
in contrast, shared considerable variance with measures from other tests, and there were no unique, or independent, age-related
effects on these measures. The results highlight the need to distinguish between process purity and the uniqueness of age-related
influences in accounting for age differences in cognition.
Memory and cognitive function are known to decline in normal aging. This impairment is due both to inevitable biologic attrition of brain function and to intercurrent disease processes. Memory storage, speed of response, channel capacity, and Performance IQ on the Wechsler Adult Intelligence Scale tend to be most impaired; Verbal IQ and previously learned skills (“crystallized intelligence”) tend to be preserved. Differences between individuals, independent of age, are often more significant than age‐related losses until very advanced age. The biases of cross‐sectional and longitudinal studies may exaggerate or minimize age‐related differences and should be recognized.
About 20 min prior to training in a shock-motivated 14-unit T-maze, young (3–4 months) and aged (24–25 months) male Fischer-344 rats were given s.c. injections of either saline or dizocilpine (MK-801, 0.02 or 0.04 mg/kg), a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor. The aged rats showed a dose-dependent impairment in maze performance. Deficiencies were manifested as increases in errors, in runtime from start to goal, and in the number and duration of shocks received. In contrast, young rats exhibited no detrimental effects of dizocilpine on maze performance. Analysis of [3H]glutamate binding in these rats revealed a marked age-related decline in NMDA receptor binding in hippocampus. A significant correlation was observed between errors in the maze and hippocampal [3H]glutamate binding, but the correlation was positive, i.e., rats that made the most errors had the highest level of NMDA receptor binding. Thus, compared to young rats, aged rats were more sensitive to the behavioral effects of NMDA receptor antagonism and they showed a hippocampal loss of [3H]glutamate in binding, which may be related to the increased sensitivity to dizocilpine. The positive correlation between poor maze performance and NMDA receptor binding suggests that the behaviors assessed involve complex interactions between NMDA receptors and other neuronal systems in the hippocampus.
Long-term potentiation (LTP) has for a long time captured the imagination of neuroscientists as a model with which to probe the cellular mechanisms of learning and memory in the mammalian brain. In this article we describe the recent evidence that has revealed the pivotal role of NMDA receptors in the induction of LTP, and discuss the possible mechanisms involved in the maintenance of the potentiated state.
Fifteen normal volunteers were administered placebo, 0.250, 0.375 and 0.500 mg of triazolam in a double- blind cross-over design. Triazolam induced robust dose-dependent impairments in explicit memory of information presented after drug administration. Subjects were unaware of their memory deficit (an impairment in meta-cognition). In contrast, memory for information presented prior to the administration of triazolam was facilitated following the administration of low doses of triazolam. Implicit memory and access to knowledge memory was unaltered by this benzodiazepine. An analysis of these results controlling for concurrent sedation as measured subjectively, through the use of self rating scales and objectively, based upon psychomotor performance, demonstrated that the amnestic effects of triazolam are largely independent of sedative effects. The pattern of memory changes induced by benzodiazepines, such as triazolam, is similar to the memory inpairment expressed in amnestic patients but unlike the pattern of impaired memory evident in dementia such as Alzheimer's disease.
Administered 16 visual analog scales to 8 normal Ss to test the validity of the scales in measuring drug effects; Ss received 150 mg of butobarbitone sodium, 15 and 30 mg of flurazepam, and a placebo. Results indicate that (a) there were no significant effects on Factor 1 (Alertness), but there was a tendency for Ss to rate themselves as more alert after placebo; (b) there was a significant Drug * Times interaction effect on Factor 2 (Contentedness); and (c) Factor 3 (Calmness) also showed a significant Drug * Times interaction effect which was caused by the anti-anxiety effect of flurazepam. (15 ref) (PsycINFO Database Record (c) 2004 APA, all rights reserved)
Modulation of glycine concentrations in the brain influences learning and memory functions in experimental animals. We administered milacemide, a glycine prodrug, or placebo to young and older healthy adults, who performed a word-retrieval task. Milacemide administration increased the number of words retrieved and decreased the latency with which these words were retrieved for both young and older adults.
D-Cycloserine is a partial agonist at the strychnine-insensitive neuronal glycine receptor and positively modulates the N-methyl-D-aspartate (NMDA) excitatory amino acid receptor. NMDA receptors appear to be important in learning and memory, and D-cycloserine facilitates learning in rats. In man, central cholinergic blockade due to scopolamine administration impairs attention, information processing, and memory for new information, the latter secondary memory impairments resembling those shown in patients with Alzheimer's disease (AD). D-Cycloserine has been studied for its ability to counteract the cognitive decrements produced by scopolamine in young and elderly healthy volunteers. D-Cycloserine specifically antagonized the memory impairments produced by scopolamine. These findings provide evidence of NMDA receptor involvement in human memory and suggest a novel mechanism for alleviation of memory loss associated with aging and dementia.
Cortical inhibitory neurotransmitters, neuropeptides, dopamine and noradrenaline are probably either not selectively or not critically affected in AD. It is, however, likely that a key change is shrinkage or loss of corticocortical pyramidal neurones, which probably use glutamate as their transmitter. This depletion appears to be circumscribed and clinically relevant.
The ability to access and use semantic knowledge was examined in 25 patients with Alzheimer's disease (AD) and 31 healthy controls. The AD patients exhibited intact automatic activation of semantic relationships on a semantic priming task. They also made active use of category information on a recognition memory test. However, the patients did not use semantic information to generate expectations on the semantic priming task and were inconsistent in their use of category information on the memory test. It is suggested that attentional deficits underlie the observed impairments and may in fact help explain the patterns of performance across tasks differing widely in their overt cognitive demands.
The N-methyl-D-aspartate receptor complex appears to play an important role in processes of learning and memory. The presence of a glycine modulatory site at this complex has recently been established and suggests that glycinergic neurotransmission may influence these cognitive functions. Increasing glycine concentrations in the brain by administration of a glycine prodrug, milacemide, is shown here to enhance performance of a shock-motivated passive avoidance task in rats, and to reverse drug-induced amnesia in a spontaneous alternation paradigm in mice. Prevention of the metabolism of milacemide to glycine by pretreatment with MAO-B inhibitors not only prevents the memory-enhancing effects of the drug, but appears to have a deleterious effect on memory formation suggesting an action of the prodrug itself on the brain. These studies indicate a role of glycinergic neurotransmission in memory processes, and support the therapeutic potential of glycinergic drugs in memory impairment.
Glycine has recently been shown to positively modulate the N-methyl-D-aspartate (NMDA) subclass of acidic amino acid receptors which are important in neural pathways involved in learning and memory. We report that d-cycloserine (DCS), an antimycobacterial agent known to cross the blood-brain barrier, binds with high affinity to this glycine modulatory site, functions as a positive modulator, and facilitates performance of learning tasks in rats. In addition, DCS appears to be a potent cognitive enhancer at doses lower than those required for antibacterial activity. Based on these data, we propose that modulation of NMDA receptors via glycinergic mechanisms may be a means of influencing cognitive processes.
Patients who have suffered concussion are for a period unable to process information at a normal rate. The time taken to recover is related to the severity of the injury, judged from the duration of post-traumatic amnesia, and after uncomplicated concussion is usually less than thirty-five days. Patients with post-concussion symptoms, who complain of inability to carry out normal work, poor concentration, fatigue, irritability, and headache, show a reduction of information-processing rate which is inappropriate to the time elapsed since injury and which persists beyond the usual period of thirty-five days. It is suggested that reduction of information-processing rate is an important factor in the genesis of the post-concussion syndrome.
Signal detection analysis was used to examine the effects of nicotine on a visual vigilance task. Groups of light, heavy and non-smokers performed the 80-min task on three separate occasions, and received different doses of nicotine each time. For all three types of smoker, nicotine significantly counteracted the decrement in stimulus sensitivity which occurred over time in the placebo condition, while having no effect on response bias. We argue that nicotine produced this effect by acting on the central, cholinergic pathways controlling electrocortical arousal, and therefore that these pathways play a role in the control of human information processing.
Patients with obstructive sleep apnea or narcolepsy report difficulty remaining alert and attentive. To detect impaired vigilance, we designed Steer Clear, a computer program simulating a long and monotonous highway drive that presents 780 obstacles in 30 min. Sixty-two patients with sleep apnea hit a higher percentage of obstacles (4.3 +/- 0.6% [SEM]) than 12 age- and sex-matched subjects without sleep apnea (1.4 +/- 0.3%; p < 0.05) and 10 age- and sex-matched volunteers (1.2 +/- 0.3%; p < 0.05). Ten patients with untreated narcolepsy hit a higher percentage of obstacles while performing on Steer Clear (7.7 +/- 3.2%) than 10 age- and sex-matched subjects without narcolepsy (1.2 +/- 0.3%; p < 0.05). Poor performance on Steer Clear was associated with a higher auto accident rate in the patients with sleep apnea or narcolepsy (p < 0.01). Twenty-one patients who performed normally on Steer Clear had 1 accident in 5 years (0.05 accident/driver/5 yr), and in none of these accidents were they at fault as drivers. Twenty-five patients who performed poorly on Steer Clear had 5 auto accidents in 5 years (0.20 accident/driver/5 yr), and in 20% of these accidents they were at fault as drivers. Twenty-one patients who performed very poorly on Steer Clear had 8 auto accidents in 5 years (0.38 accident/driver/5 yr), and in 38% of these accidents they were at fault as drivers. These 21 patients who performed very poorly on Steer Clear (hitting > 4.5% of obstacles) had a significantly higher auto accident rate than the patients who performed normally (hitting < 1.8%). We conclude: (1) Patients with sleep apnea or narcolepsy performed more poorly on a test of vigilance, Steer Clear, than did control subjects; (2) Impaired vigilance as measured by Steer Clear is associated with a high automobile accident rate in patients with either sleep apnea or narcolepsy.
Synopsis
Until very recently, memory impairment was not considered to be a central feature of schizophrenia, except in chronic, deteriorated patients. In this study of a heterogeneous sample of 40 patients with DSM-III-R schizophrenia, episodic memory impairment was found to be prevalent, and in some cases, severe. The degree of memory impairment was not attributable to neuroleptic or anticholinergic medication, or to poor motivation or cooperation. These results, therefore, replicate those reported by McKenna et al. (1990) and Tamlyn et al. (1992), who suggested that the pattern of memory impairment in schizophrenia may conform in important respects to that of the classic amnesic syndrome. However, in a direct comparison of the schizophrenic sample with 18 patients suffering from the Alcoholic Korsakoff Syndrome (AKS), both quantitative and qualitative differences were found to exist between the two groups of patients. In particular, the level of long-term episodic memory impairment was found in the AKS sample to be far greater than that in the schizophrenic group. An interesting possible double-dissociation emerged between the two groups; although demonstrating superior episodic memory functioning, the schizophrenic sample were found to perform significantly more poorly than the AKS sample on a test of semantic memory.
• Objective.
—Comparing the pattern of spared and impaired memory functions in neurodegenerative diseases known to affect different brain structures.Design.
—Various situations of acquisition (free encoding or controlled encoding) and retrieval (immediate and delayed free and cued recall, recognition) were used.Setting.
—Referral center.Patients.
—Fifteen for each disease (ie, senile dementia of the Alzheimer type [SDAT], Parkinson's, and Huntington's), matched for education, severity of dementia, and depression.Main Outcome Measures.
—Comparison of free and controlled encoding situations, relationships between memory, executive, and linguistic functions test scores.Results.
—In the free encoding situation: no difference among the three groups, but higher numbers of intrusions and false recognitions in SDAT. In the controlled situation: cued recall and recognition scores significantly higher in Parkinson's disease and Huntington's disease than in SDAT. Memory performances correlated with executive functions test scores in Huntington's disease and Parkinson's disease, but not in SDAT. All results significant at P<.01.Conclusions.
—Clear distinction between the true amnesic syndrome of SDAT, compatible with lesions of hippocampus and temporal cortex, and the inefficient planning of memory processes of Huntington's disease and Parkinson's disease, which might result from a striatofrontal dysfunction.
We tested the ability of d-cycloserine, a partial glycine agonist acting at the N-methyl-D-aspartate (NMDA) receptor complex, to improve implicit memory in Alzheimer patients in a parallel-group, placebo-controlled, double-blind study. One-hundred eight patients with probable Alzheimer's disease of mild to moderate severity received d-cycloserine (5, 15, or 50 mg) or placebo twice daily for 10 weeks. We then evaluated their ability to identify perceptually degraded words, some of which were repeated over multiple trials across 3 days. Implicit memory performance of words repeated across trials was significantly enhanced for the patients who received 15 mg d-cycloserine compared with those who received placebo. These findings support development of NMDA receptor-mediated glutamatergic interventions for the treatment of Alzheimer-related memory disorders.
It has been proposed that schizophrenia is associated with underactivity of brain glutamatergic neurotransmission, especially at the level of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Glycine potentiates NMDA receptor-mediated neurotransmission, indicating that it may serve as an effective therapeutic agent in the treatment of schizophrenia.
Eleven treatment-resistant patients with chronic schizophrenia completed a double-blind, placebo-controlled, six-week, randomly assigned, crossover treatment trial of 0.8 g/kg body weight/day of glycine, added to their prior antipsychotic treatment.
Glycine was well tolerated, resulted in significantly increased serum glycine levels and induced a mean 36 (7%) reduction in negative symptoms (P < 0.0001). Significant improvements were also induced in depressive and cognitive symptoms. The greatest reduction in negative symptoms was registered in the patients who had the lowest baseline serum glycine levels.
These results extend previous findings and suggest an additional approach to the pharmacotherapy of negative symptoms and cognitive deficits in schizophrenia.
This study examined the effects of dual task requirements on age differences in free recall performance. One thousand adults ranging in age between 35 and 80 years performed a word recall task alone and concurrently with a card-sorting task (at encoding, retrieval, or both). Age differences in memory performance were substantial under single task conditions, but after correcting memory performance under dual task conditions for differences in single task performance, age did not predict performance. These results do not support the hypothesis that reduced attentional capacity in old age is underlying age differences in episodic memory.
Performances of 12 patients with Alzheimer's disease (AD), 15 healthy elderly subjects and 20 young healthy volunteers were compared on two episodic memory tests. The first, a learning test of semantically related words, enabled an assessment of the effect of semantic relationships on word learning by controlling the encoding and retrieval processes. The second, a dual coding test, is about the assessment of automatic processes operating during drawings encoding. The results obtained demonstrated quantitative and qualitative differences between the population. Manifestations of episodic memory deficit in AD patients were shown not only by lower performance scores than in elderly controls, but also by the lack of any effect of semantic cues and the production of a large number of extra-list intrusions. Automatic processes underlying dual coding appear to be spared in AD, although more time is needed to process information than in young or elderly subjects. These findings confirm former data and emphasize the preservation of certain memory processes (dual coding) in AD which could be used in future therapeutic approaches.
In a previous study we reported that the affinity of the platelet benzodiazepine receptor was greater in alcoholic cirrhotic patients compared with normal controls and that there were detectable ligands for the neuronal benzodiazepine receptor in plasma from both alcoholic and nonalcoholic cirrhotic patients. The aim of the present study was to assess the separate contributions of alcoholism and cirrhosis to the presence of ligands in plasma for the neuronal and peripheral benzodiazepine receptors and to changes in peripheral benzodiazepine receptor binding in platelets. These parameters were measured in 10 alcoholic cirrhotics, 9 nonalcoholic cirrhotics, 7 alcoholics with a normal liver function, and 15 nonalcoholic subjects and normal liver function. Both groups of alcoholics had been abstinent for several months and the nonalcoholic groups had abstained for 24 h before the study. The concentration of ligands for the peripheral benzodiazepine receptor were significantly higher in both cirrhotic groups compared with the other two groups, suggesting that cirrhosis was responsible for this accumulation. Furthermore, the cirrhotic patients with detectable concentrations of these ligands had significantly poorer episodic memory than those without ligands. However, the presence of ligands for the peripheral benzodiazepine receptor did not correlate with the change in receptor affinity, which was increased in the alcoholic cirrhotic group compared with all other groups. Neither cirrhosis nor alcoholism altered the peripheral benzodiazepine receptor number. The cirrhotic patients with detectable ligands for the neuronal benzodiazepine receptor showed psychomotor slowing and executive dysfunction. The results suggest that the ligands for the peripheral benzodiazepine receptor may contribute to some of the cognitive deficits seen in hepatic encephalopathy, but are not responsible for the receptor affinity change seen in the alcoholic cirrhotics. This affinity change is not solely due to the effects of alcohol and could possibly serve as a marker for those at risk for developing alcoholic cirrhosis.
It is notoriously difficult to assess the contribution of the sedative effects of benzodiazepines to the cognitive impairments that they produce. The purpose of the present experiment was to determine whether a similar pattern of cognitive impairment would be seen in conditions when subjects felt equally sleepy as the result of sleep deprivation. The effects of a sedative dose of lorazepam (2.5 mg) in healthy volunteers was therefore compared with the effects of acute sleep deprivation (a night on-call) in a group of junior doctors and the effects of chronically disturbed sleep due to snoring. Lorazepam, acute sleep deprivation, and chronic sleep disturbance all significantly increased subjective sedation. In addition, lorazepam significantly impaired performance in two tests of psychomotor speed and caused significant anterograde amnesia. Semantic and short-term memory were not impaired by lorazepam, nor was there any impairment in executive function. The only deficit found following acute sleep deprivation was in a test of semantic memory, generating examples from a difficult category. The only significant deficit in the group suffering from chronically disturbed sleep, compared with age-matched controls, was in executive function, and there was a nearly significant impairment in sustained attention. These results suggest that, despite the common factor of increased subjective sedation, the profile of cognitive impairment in the two sleep deprivation groups are neither similar to each other nor to that seen following an acute dose of lorazepam.
Memory is composed of three stages: acquisition, consolidation, and retrieval. By impairing acquisition processes, benzodiazepines cause anterograde amnesia while leaving intact information learned before the drug was taken. In some circumstances, retrieval of this information is even improved by benzodiazepines. It has been hypothesized that this phenomenon is not a true facilitation of retrieval processes, but is the result of reduced interference from items presented after drug administration and is thus a secondary consequence of drug-induced amnesia. Experiment 1 investigated the effect of 0.5, 1, and 2.5 mg of lorazepam on explicit episodic memory in healthy young volunteers. The 1-mg dose was found to significantly improve recall of items presented before drug administration without causing amnesia for items presented after drug administration, thus excluding an interference explanation. Experiment 2 investigated the conditions necessary to obtain facilitated retrieval with 1 mg of lorazepam. The results showed that facilitation was found only when two lists of semantically related material were presented, but that both of the lists could be presented before drug administration, thus excluding an effect of lorazepam on consolidation. Facilitation could be demonstrated in both direct (free recall) and indirect (backwards reading) retrieval tasks and when all of the material was presented after lorazepam administration. This improved retrieval could therefore be of clinical relevance, but any benefits would be reduced at higher doses that at the same time impair acquisition of new information. However, because 1 mg of lorazepam is an effective anxiolytic dose, these results suggest that it is possible to combine effective anxiety reduction with some benefits to memory.
- Salthouse
- Lafosse