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1.
Phosphodiesterase as a Target for Cognition Enhancement in Schizophrenia.
Al-Nema, MY, Gaurav, A
Current topics in medicinal chemistry. 2020;(26):2404-2421
Abstract
Schizophrenia is a severe mental disorder that affects more than 1% of the population worldwide. Dopamine system dysfunction and alterations in glutamatergic neurotransmission are strongly implicated in the aetiology of schizophrenia. To date, antipsychotic drugs are the only available treatment for the symptoms of schizophrenia. These medications, which act as D2-receptor antagonist, adequately address the positive symptoms of the disease, but they fail to improve the negative symptoms and cognitive impairment. In schizophrenia, cognitive impairment is a core feature of the disorder. Therefore, the treatment of cognitive impairment and the other symptoms related to schizophrenia remains a significant unmet medical need. Currently, phosphodiesterases (PDEs) are considered the best drug target for the treatment of schizophrenia since many PDE subfamilies are abundant in the brain regions that are relevant to cognition. Thus, this review aims to illustrate the mechanism of PDEs in treating the symptoms of schizophrenia and summarises the encouraging results of PDE inhibitors as anti-schizophrenic drugs in preclinical and clinical studies.
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Effects of Rice Wine Lees on Cognitive Function in Community-Dwelling Physically Active Older Adults: A Pilot Randomized Controlled Trial.
Nagai, N, Shindo, N, Wada, A, Izu, H, Fujii, T, Matsubara, K, Wada, Y, Sakane, N
The journal of prevention of Alzheimer's disease. 2020;(2):95-103
Abstract
BACKGROUND Rice wine lees (RWL), a Japanese traditional fermented product, is a rich source of one-carbon metabolism-related nutrients, which may have beneficial effects on cognitive function. OBJECTIVES We aimed to examine the effect of the RWL on cognitive function in community-dwelling physically active older adults. DESIGN Double-blind, randomized, placebo-controlled study (clinical trial number: UMIN 000027158). SETTING Community-based intervention including assessments conducted at the University of Hyogo and a public liberal arts school in Himeji City, Japan. PARTICIPANTS A total of 35 community-dwelling older adults (68-80 years) who performed mild exercise before and during the trial were assigned to either the RWL (n=17) or the placebo group (n=18). INTERVENTION Daily consumption of 50 g RWL powder, which contained one-carbon metabolism-related nutrients, or the placebo powder (made from soy protein and dextrin) for 12 weeks. Both supplements included equivalent amounts of energy and protein. MEASUREMENTS Montreal Cognitive Assessment, computerized cognitive function test, and measurements of serum predictive biomarkers (transthyretin, apolipoprotein A1, and complement C3) were conducted at baseline and follow-up. RESULTS Visual selective attention and serum transthyretin significantly improved in the RWL group, whereas there was no significant change in the placebo group. No significant group difference was observed in the remaining cognitive performance tests. CONCLUSIONS RWL supplements seem to have a few effects on cognitive function in community-dwelling physically active older adults. However, the impact was limited; therefore, further studies with sufficient sample size are warranted to elucidate this issue.
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Potential effect of herbal antidepressants on cognitive deficit: Pharmacological activity and possible molecular mechanism.
Li, JM, Zhao, Y, Sun, Y, Kong, LD
Journal of ethnopharmacology. 2020;:112830
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cognitive symptom is a "core" symptom of major depressive disorder (MDD) patients with clear deficit in memory, social and occupational function, and may persist during the remitting phase. Therefore, the remission of cognitive symptom has been considered as one of the main objectives in the treatment of MDD. Herbal antidepressants have been used to treat MDD, and there has been great advances in the understanding of the ability of these herbs to improve cognitive deficit linked to brain injury and various diseases including depression, Alzheimer disease, diabetes and age-related disorders. This systematic review summarizes the evidence from preclinical studies and clinical trials of herbal antidepressants with positive effects on cognitive deficit. The potential mechanisms by which herbal antidepressants prevent cognitive deficit are also reviewed. This review will facilitate further research and applications. MATERIALS AND METHODS We conducted an open-ended, English restricted search of MEDLINE (PubMed), Web of Science and Scopus for all available articles published or online before 31 December 2019, using terms pertaining to medical herb/phytomedicine/phytochemical/Chinese medicine and depression/major depressive disorder/antidepressant and/or cognitive impairment/cognitive deficit/cognitive dysfunction. RESULTS 7 prescriptions, more than 30 individual herbs and 50 phytochemicals from China, Japan, Korea and India with positive effects on the depressive state and cognitive deficit are reviewed herein. The evidence from preclinical studies and clinical trials proves that these herbal antidepressants exhibit positive effects on one or more aspects of cognitive defect including spatial, episodic, aversive, and short- and long-term memory. The action mode of the improvement of cognitive deficit by these herbal antidepressants is mediated mainly through two pathways. One pathway is to promote hippocampal neurogenesis through activating brain derived neurotrophic factor-tropomyosin-related kinase B signaling. The other pathway is to prevent neuronal apoptosis through the inhibition of neuro-inflammation and neuro-oxidation. CONCLUSION These herbal antidepressants, having potential therapy for cognitive deficit, may prevent pathological processes of neurodegenerative diseases. Furthermore, these herbal medicines should provide a treasure trove, which will accelerate the development of new antidepressants that can effectively improve cognitive symptom in MDD. Studies on their molecular mechanisms may provide more potential targets and therapeutic approaches for new drug discovery.
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Cerebrovascular risk factors impact frontoparietal network integrity and executive function in healthy ageing.
Veldsman, M, Tai, XY, Nichols, T, Smith, S, Peixoto, J, Manohar, S, Husain, M
Nature communications. 2020;(1):4340
Abstract
Healthy cognitive ageing is a societal and public health priority. Cerebrovascular risk factors increase the likelihood of dementia in older people but their impact on cognitive ageing in younger, healthy brains is less clear. The UK Biobank provides cognition and brain imaging measures in the largest population cohort studied to date. Here we show that cognitive abilities of healthy individuals (N = 22,059) in this sample are detrimentally affected by cerebrovascular risk factors. Structural equation modelling revealed that cerebrovascular risk is associated with reduced cerebral grey matter and white matter integrity within a fronto-parietal brain network underlying executive function. Notably, higher systolic blood pressure was associated with worse executive cognitive function in mid-life (44-69 years), but not in late-life (>70 years). During mid-life this association did not occur in the systolic range of 110-140 mmHg. These findings suggest cerebrovascular risk factors impact on brain structure and cognitive function in healthy people.
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Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Extremely Low-Birth-Weight Infants: The ETTNO Randomized Clinical Trial.
Franz, AR, Engel, C, Bassler, D, Rüdiger, M, Thome, UH, Maier, RF, Krägeloh-Mann, I, Kron, M, Essers, J, Bührer, C, et al
JAMA. 2020;(6):560-570
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Abstract
IMPORTANCE Red blood cell transfusions are commonly administered to infants weighing less than 1000 g at birth. Evidence-based transfusion thresholds have not been established. Previous studies have suggested higher rates of cognitive impairment with restrictive transfusion thresholds. OBJECTIVE To compare the effect of liberal vs restrictive red blood cell transfusion strategies on death or disability. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted in 36 level III/IV neonatal intensive care units in Europe among 1013 infants with birth weights of 400 g to 999 g at less than 72 hours after birth; enrollment took place between July 14, 2011, and November 14, 2014, and follow-up was completed by January 15, 2018. INTERVENTIONS Infants were randomly assigned to liberal (n = 492) or restrictive (n = 521) red blood cell transfusion thresholds based on infants' postnatal age and current health state. MAIN OUTCOME AND MEASURES The primary outcome, measured at 24 months of corrected age, was death or disability, defined as any of cognitive deficit, cerebral palsy, or severe visual or hearing impairment. Secondary outcome measures included individual components of the primary outcome, complications of prematurity, and growth. RESULTS Among 1013 patients randomized (median gestational age at birth, 26.3 [interquartile range {IQR}, 24.9-27.6] weeks; 509 [50.2%] females), 928 (91.6%) completed the trial. Among infants in the liberal vs restrictive transfusion thresholds groups, respectively, incidence of any transfusion was 400/492 (81.3%) vs 315/521 (60.5%); median volume transfused was 40 mL (IQR, 16-73 mL) vs 19 mL (IQR, 0-46 mL); and weekly mean hematocrit was 3 percentage points higher with liberal thresholds. Among infants in the liberal vs restrictive thresholds groups, the primary outcome occurred in 200/450 (44.4%) vs 205/478 (42.9%), respectively, for a difference of 1.6% (95% CI, -4.8% to 7.9%; P = .72). Death by 24 months occurred in 38/460 (8.3%) vs 44/491 (9.0%), for a difference of -0.7% (95% CI, -4.3% to 2.9%; P = .70), cognitive deficit was observed in 154/410 (37.6%) vs 148/430 (34.4%), for a difference of 3.2% (95% CI, -3.3% to 9.6%; P = .47), and cerebral palsy occurred in 18/419 (4.3%) vs 25/443 (5.6%), for a difference of -1.3% (95% CI, -4.2% to 1.5%; P = .37), in the liberal vs the restrictive thresholds groups, respectively. In the liberal vs restrictive thresholds groups, necrotizing enterocolitis requiring surgical intervention occurred in 20/492 (4.1%) vs 28/518 (5.4%); bronchopulmonary dysplasia occurred in 130/458 (28.4%) vs 126/485 (26.0%); and treatment for retinopathy of prematurity was required in 41/472 (8.7%) vs 38/492 (7.7%). Growth at follow-up was also not significantly different between groups. CONCLUSIONS AND RELEVANCE Among infants with birth weights of less than 1000 g, a strategy of liberal blood transfusions compared with restrictive transfusions did not reduce the likelihood of death or disability at 24 months of corrected age. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01393496.
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Differential effects of cognitive training modules in healthy aging and mild cognitive impairment: A comprehensive meta-analysis of randomized controlled trials.
Basak, C, Qin, S, O'Connell, MA
Psychology and aging. 2020;(2):220-249
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Abstract
This meta-analysis was designed to compare the effectiveness of 2 cognitive training modules, single-component training, which targets 1 specific cognitive ability, versus multicomponent training, which trains multiple cognitive abilities, on both trained abilities (near transfer) and untrained abilities (far transfer) in older adults. The meta-analysis also assessed whether individual differences in mental status interacted with the extent of transfer. Eligible randomized controlled trials (215 training studies) examined the immediate effects of cognitive training in either healthy aging (HA) or mild cognitive impairment (MCI). Results yielded an overall net-gain effect size (g) for the cognitive training of 0.28 (p < .001). These effects were similar across mental status and training modules, and were significant for both near (g = 0.37) and far (g = 0.22) transfer. Although all training modules yielded significant near transfer, only a few yielded significant far transfer. Single-component training of executive functions was most effective on near and far transfer, with processing speed training improving everyday functioning. All modules of multicomponent training (specific and nonspecific) yielded significant near and far transfer, including everyday functioning. Training effects on cognition were moderated by educational attainment and number of cognitive outcomes, but only in HA. These findings suggest that, in older adults, all modules of multicomponent training are more effective in engendering near and far transfer, including everyday functioning, when compared with single-component training modules. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
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Homocysteine: A modifiable culprit of cognitive impairment for us to conquer?
Ji, Y, Lyu, P, Jin, W, Li, X, Li, X, Dong, Y
Journal of the neurological sciences. 2019;:128-136
Abstract
BACKGROUND Cognitive impairment, including mild cognitive impairment and its progressive deterioration to dementia, results in great hazards to the patient and the surrounding society. While some of the risk factors are unmodifiable, such as age, lower educational attainment, and genetic factors, another proposed one-homocysteine, an amino acid produced in the methylation cycle of protein metabolism is modifiable by cheap and easily accessible B-vitamins treatments in medical practice. OBJECTIVE AND METHODS To investigate the relationship between homocysteine and cognitive impairment, elucidate the underlying pathophysiological mechanisms and exploit any potential therapeutic values of homocysteine-lowering treatments in prevention and/or treatment in cognitive decline, we searched on the PUBMED databases surrounding around the physiological homocysteine metabolism, detrimental effects of abnormal homocysteine concentrations on the brain, and review observational and interventional experiments to date estimating the relationship between homocysteine and cognitive impairment with relatively powerful evidence. RESULTS Intrinsic and environmental factors help maintain the normal homocysteine concentrations, and pathological homocysteine concentrations exert adverse effects mediated by cellular and vascular pathways. Although many observational studies have suggested a causal link between hyperhomocysteinemia and cognitive impairment, the majority of randomized controlled trials failed to observe marked benefits on cognition by homocysteine-lowering treatments using B-vitamins, partly arising from some design limitations including: not identifying individuals at earlier stages of cognitive impairment who are most likely to benefit, overlooking any latent safety hazards of multiple vitamin supplementation, lack of sensitive and domain-specific cognitive tests, and interference of other underappreciated factors. CONCLUSION More studies are required to better explain the related pathophysiological mechanisms, improve experimental methods, and investigate the preventive or/and therapeutic effects of homocysteine-lowering strategies on cognitive impairment.
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MIND not Mediterranean diet related to 12-year incidence of cognitive impairment in an Australian longitudinal cohort study.
Hosking, DE, Eramudugolla, R, Cherbuin, N, Anstey, KJ
Alzheimer's & dementia : the journal of the Alzheimer's Association. 2019;(4):581-589
Abstract
INTRODUCTION Associations between the Mediterranean-DASH diet Intervention for Neurological Delay (MIND) diet and incidence of cognitive impairment have not been evaluated outside the United States. METHODS We investigated MIND and Mediterranean diet relations with 12-year incidence of Alzheimer's disease/Vascular dementia (National Institute of Neurological Disorders criteria) and mild cognitive impairment (Winbald criteria) in the Personality and Total Health (PATH) Through Life cohort (n = 1220) set in Canberra, Australia: wave-1 2001-2002; wave-2 2005-2006; wave-3 2009-2010; and wave-4 2013-2014. MIND diet and two alternate Mediterranean diet scores were calculated from the baseline food frequency questionnaire responses. Higher dietary scores signified greater adherence. RESULTS In adjusted logistic regression models, MIND diet (OR = 0.47, 95% CI 0.24, 0.91), but not Mediterranean diet, was associated with reduced odds of 12-year cognitive impairment. DISCUSSION Preliminary evidence suggests that protective effects of the MIND diet are geographically generalizable. Additional prospective studies are needed in diverse samples to determine the relative effects of the MIND and the Mediterranean diets against cognitive decline.
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Vitamin and mineral supplementation for preventing dementia or delaying cognitive decline in people with mild cognitive impairment.
McCleery, J, Abraham, RP, Denton, DA, Rutjes, AW, Chong, LY, Al-Assaf, AS, Griffith, DJ, Rafeeq, S, Yaman, H, Malik, MA, et al
The Cochrane database of systematic reviews. 2018;(11):CD011905
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BACKGROUND Vitamins and minerals have many functions in the nervous system which are important for brain health. It has been suggested that various different vitamin and mineral supplements might be useful in maintaining cognitive function and delaying the onset of dementia. In this review, we sought to examine the evidence for this in people who already had mild cognitive impairment (MCI). OBJECTIVES To evaluate the effects of vitamin and mineral supplementation on cognitive function and the incidence of dementia in people with mild cognitive impairment. SEARCH METHODS We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's (CDCIG) specialised register, as well as MEDLINE, Embase, PsycINFO, CENTRAL, CINAHL, LILACs, Web of Science Core Collection, ClinicalTrials.gov, and the WHO Portal/ICTRP, from inception to 25 January 2018. SELECTION CRITERIA We included randomised or quasi-randomised, placebo-controlled trials which evaluated orally administered vitamin or mineral supplements in participants with a diagnosis of mild cognitive impairment and which assessed the incidence of dementia or cognitive outcomes, or both. We were interested in studies applicable to the general population of older people and therefore excluded studies in which participants had severe vitamin or mineral deficiencies. DATA COLLECTION AND ANALYSIS We sought data on our primary outcomes of dementia incidence and overall cognitive function and on secondary outcomes of episodic memory, executive function, speed of processing, quality of life, functional performance, clinical global impression, adverse events, and mortality. We conducted data collection and analysis according to standard Cochrane systematic review methods. We assessed the risk of bias of included studies using the Cochrane 'Risk of bias' assessment tool. We grouped vitamins and minerals according to their putative mechanism of action and, where we considered it to be clinically appropriate, we pooled data using random-effects methods. We used GRADE methods to assess the overall quality of evidence for each comparison and outcome. MAIN RESULTS We included five trials with 879 participants which investigated B vitamin supplements. In four trials, the intervention was a combination of vitamins B6, B12, and folic acid; in one, it was folic acid only. Doses varied. We considered there to be some risks of performance and attrition bias and of selective outcome reporting among these trials. Our primary efficacy outcomes were the incidence of dementia and scores on measures of overall cognitive function. None of the trials reported the incidence of dementia and the evidence on overall cognitive function was of very low-quality. There was probably little or no effect of B vitamins taken for six to 24 months on episodic memory, executive function, speed of processing, or quality of life. The evidence on our other secondary clinical outcomes, including harms, was very sparse or very low-quality. There was evidence from one study that there may be a slower rate of brain atrophy over two years in participants taking B vitamins. The same study reported subgroup analyses based on the level of serum homocysteine (tHcy) at baseline and found evidence that B vitamins may improve episodic memory in those with tHcy above the median at baseline.We included one trial (n = 516) of vitamin E supplementation. Vitamin E was given as 1000 IU of alpha-tocopherol twice daily. We considered this trial to be at risk of attrition and selective reporting bias. There was probably no effect of vitamin E on the probability of progression from MCI to Alzheimer's dementia over three years (HR 1.02; 95% CI 0.74 to 1.41; n = 516; 1 study, moderate-quality evidence). There was also no evidence of an effect at intermediate time points. The available data did not allow us to conduct analyses, but the authors reported no significant effect of three years of supplementation with vitamin E on overall cognitive function, episodic memory, speed of processing, clinical global impression, functional performance, adverse events, or mortality (five deaths in each group). We considered this to be low-quality evidence.We included one trial (n = 256) of combined vitamin E and vitamin C supplementation and one trial (n = 26) of supplementation with chromium picolinate. In both cases, there was a single eligible cognitive outcome, but we considered the evidence to be very low-quality and so could not be sure of any effects. AUTHORS' CONCLUSIONS The evidence on vitamin and mineral supplements as treatments for MCI is very limited. Three years of treatment with high-dose vitamin E probably does not reduce the risk of progression to dementia, but we have no data on this outcome for other supplements. Only B vitamins have been assessed in more than one RCT. There is no evidence for beneficial effects on cognition of supplementation with B vitamins for six to 24 months. Evidence from a single study of a reduced rate of brain atrophy in participants taking vitamin B and a beneficial effect of vitamin B on episodic memory in those with higher tHcy at baseline warrants attempted replication.
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Diet, nutrition and the ageing brain: current evidence and new directions.
Moore, K, Hughes, CF, Ward, M, Hoey, L, McNulty, H
The Proceedings of the Nutrition Society. 2018;(2):152-163
Abstract
Globally populations are ageing. By 2050, it is estimated that there will be two billion people aged 60 years or over, of which 131 million are projected to be affected by dementia, while depression is predicted to be the second leading cause of disability worldwide by 2020. Preventing or delaying the onset of these disorders should therefore be a public health priority. There is some evidence linking certain dietary patterns, particularly the Mediterranean diet, with a reduced risk of dementia and depression. Specific dietary components have also been investigated in relation to brain health, with emerging evidence supporting protective roles for n-3 PUFA, polyphenols, vitamin D and B-vitamins. At this time, the totality of evidence is strongest in support of a role for folate and the metabolically related B-vitamins (vitamin B12, vitamin B6 and riboflavin) in slowing the progression of cognitive decline and possibly reducing the risk of depression in ageing. Future studies incorporating new technologies, such as MRI and magnetoencephalography, offer much promise in identifying effective nutrition interventions that could reduce the risk of cognitive and mental disorders. This review will explore the ageing brain and the emerging evidence linking diet and specific nutrients with cognitive function and depression in ageing, with the potential to develop strategies that could improve quality of life in our ageing population.