Omega-3 fatty acids intake and risks of dementia and Alzheimer's disease: A meta-analysis

BackgroundWe systematically reviewed the association of omega-3 fatty acids intake with the incidence of dementia and Alzheimer's disease (AD) in this meta-analysis of prospective cohort studies, as evidence from previous studies suggests inconsistent results.MethodsWe identified relevant studies by searching PubMed, EmBase, and Web of Science databases up to June 2013. Prospective cohort studies reporting on associations of dietary intake of long-chain omega-3 fatty acids or fish with the incidence of dementia and AD were eligible.ResultsComparing the highest to lowest category of long-chain omega-3 fatty acids intake and fish intake, the pooled relative risks (RRs) for dementia were 0.97 (95% CI 0.85–1.10) and 0.84 (95% CI 0.71–1.01), respectively. Evidence synthesis for AD risk did not show a statistically significant association with long-chain omega-3 fatty acids intake (RR = 0.89, 95% CI 0.74–1.08). However, a higher intake of fish was associated with a 36% (95% CI 8–56%) lower risk of AD. Dose–response meta-analysis showed that an increment of 100 g per week of fish intake was associated with an 11% lower risk of AD (RR = 0.89, 95% CI 0.79–0.99). There was limited evidence of heterogeneity across studies or within subgroups.ConclusionA higher intake of fish was associated with a lower risk of AD. However, there was no statistical evidence for similar inverse association between long-chain omega-3 fatty acids intake and risk of dementia or AD, nor was there inverse association between fish intake and risk of dementia.     

Omega-3 fatty acids and antioxidants in neurological and psychiatric diseases: an overview

RATIONALE: Omega-3 fatty acids are known to play a role in nervous system activity, cognitive development, memory-related learning, neuroplasticity of nerve membranes, synaptogenesis and synaptic transmission. The brain is considered abnormally sensitive to oxidative damage, and aging is considered one of the most significant risk factors for degenerative neurological disorders. Recently, clinical trials of several neurodegenerative diseases have increasingly targeted the evaluation of the effectiveness of various antioxidants. OBJECTIVES: The effects of omega-3 fatty acids and antioxidants on the anatomic and functional central nervous system development and their possible therapeutical use in some neurological and psychiatric pathologies are evaluated. RESULTS: A number of critical trials have confirmed the benefits of dietary supplementation with omega-3 fatty acids not only in several psychiatric conditions, but also in inflammatory and autoimmune and neurodegenerative diseases. Many evidences indicate that antioxidants are also essential in maintaining a correct neurophysiology. CONCLUSIONS: Omega-3 fatty acids could be useful in the prevention of different pathologies, such as cardiovascular, psychiatric, neurological, dermatological and rheumatological disorders. A number of studies suggest that antioxidants can prevent the oxidation of various macromolecules such as DNA, proteins, and lipids. The ideal use of antioxidants should be a prophylactic and continue treatment before aging.     

Ethyl-eicosapentaenoate (E-EPA) attenuates motor impairments and inflammation in the MPTP-probenecid mouse model of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder, characterized by hypokinesia, but also mood and cognitive disorders. Neuropathologically, PD involves loss of nigrostriatal dopamine (DA) and secondary non-dopaminergic abnormalities. Inflammation may contribute to PD pathogenesis, evident by increased production of pro-inflammatory cytokines. PD onset has been positively associated with dietary intake of omega-(n)-6 polyunsaturated fatty acids (PUFA). On the other hand, omega-(n)-3 PUFA may benefit PD. One of these n-3 PUFA, eicosapentaenoic acid (EPA), is a neuroprotective lipid with anti-inflammatory properties, but its neuroprotective effects in PD are unknown. Thus, we presently tested the hypothesis that EPA can protect against behavioral impairments, neurodegeneration and inflammation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-probenecid (MPTP-P) mouse model of PD. MPTP-P injections caused hypokinesia in the rotorod and pole test, hyperactivity in the open field, and impaired mice on the cued version (procedural memory) of the Morris water maze. MPTP-P caused a loss of nigrostriatal DA and altered neurochemistry in the frontal cortex and hippocampus. Furthermore, striatal levels of pro-inflammatory cytokines were increased, while the brain n-3/n-6 lipid profile remained unaltered. Feeding mice a 0.8% ethyl-eicosapentaenoate (E-EPA) diet prior to MPTP-P injections increased brain EPA and docosapentaenoic acid (DPA) but not docosahexaenoic acid (DHA) or n-6 PUFA. The diet attenuated the hypokinesia induced by MPTP-P and ameliorated the procedural memory deficit. E-EPA also suppressed the production of pro-inflammatory cytokines. However, E-EPA did not prevent nigrostriatal DA loss. Based on this partial protective effect of E-EPA, further testing may be warranted.     

Brain uptake and utilization of fatty acids: recommendations for future research

A primary goal of the international workshop "Brain Uptake and Utilization of Fatty Acids" was to identify research areas that would benefit from further investigation. The major themes for future research are presented below: (1) Elucidating the role of the developing and mature cerebrovascular endothelium (CVE) in the uptake of fatty acids (FA) into the brain. (2) Clarifying the role of diffusion and receptor-mediated uptake of FAs by various brain cell membranes and protein-mediated shuttling of FAs between the CVE and various brain cells and tissues. (3) Illuminating the mechanisms of intermediate metabolism and the roles of polyunsaturated fatty acids (PUFA) in astrocytes, neurons and oligodendrocytes. Of special interest are the long-chain omega-3 PUFA and their derivatives, such as lipoproteins, phospholipids and plasmalogens, that have been associated with various disease states (such as those listed in [5], below). (4) Elucidating the role of gene expression on long-chain omega-3 PUFA incorporation in membranes and the regulatory role these and other PUFA have on gene expression in the brain. (5) Elucidating the recently identified roles of long-chain omega-3 PUFA in mood disorders, schizophrenia, stroke, peroxisomal biogenesis disorders, Huntington's disease, other neurodegenerative disorders and disorders of oxidative stress. (6) Undertaking placebo-controlled clinical trials to assess the therapeutic potential of omega-3 PUFA in the above disorders. (7) Developing new, and utilizing existing animal models in the above studies. (8) Developing noninvasive imaging and tagging methods for quantifying the migration and distribution of PUFA and their derivatives in the brain. (9) Applying multi-disciplinary collaborations among biophysicists, physiologists and molecular biologists to the resolution of the above.     

Brain Uptake and Utilization of Fatty Acids,Lipids and Lipoproteins: Application to Neurological Disorders

Transport, synthesis, and utilization of brain fatty acids and other lipids have been topics of investigation for more than a century, yet many fundamental aspects are unresolved and, indeed, subject to controversy. Understanding the mechanisms by which lipids cross the blood brain barrier and how they are utilized by neurons and glia is critical to understanding normal brain development and function, for the diagnosis and therapy of human diseases, and for the planning and delivery of optimal human nutrition throughout the world. Two particularly important fatty acids, both of which are abundant in neuronal membranes are: (a) the ω3 polyunsaturated fatty acid docosahexaenoic acid, deficiencies of which can impede brain development and compromise optimal brain function, and (b) the ω6 polyunsaturated fatty acid arachidonic acid, which yields essential, but potentially toxic, metabolic products. There is an exciting emerging evidence that modulating dietary intake of these fatty acids could have a beneficial effect on human neurological health. A workshop was held in October, 2004, in which investigators from diverse disciplines interacted to present new findings and to discuss issues relevant to lipid uptake, utilization, and metabolism in the brain. The objectives of this workshop were: (1) to assess the state-of-the-art of research in brain fatty acid/lipid uptake and utilization; (2) to discuss progress in understanding molecular mechanisms and the treatment of neurological diseases related to lipids and lipoproteins; (3) to identify areas in which current knowledge is insufficient; (4) to provide recommendations for future research; and (5) to stimulate the interest and involvement of additional neuroscientists, particularly young scientists, in these areas. The meeting was divided into four sessions: (1) mechanisms of lipid uptake and transport in the brain, (2) lipoproteins and polyunsaturated fatty acids, (3) eicosanoids in brain function, and (4) fatty acids and lipids in brain disorders. In this article, we will provide an overview of the topics discussed in these sessions.     

Marine n-3 polyunsaturated fatty acids and coronary heart disease. Part I. Background, epidemiology, animal data, effects on risk factors and safety

In this paper, we will give an overview of the background for the possible effects of long-chain marine n-3 (synonymously called omega-3) polyunsaturated fatty acids (PUFA) in coronary heart disease (CHD) with focus on recent findings. In a forthcoming paper, we will focus on the clinical trial data, current recommendations and suggest trials to further study the role of marine n-3 PUFA in the prevention and treatment of CHD.     

Reduced red blood cell membrane essential polyunsaturated fatty acids in first episode schizophrenia at neuroleptic-naive baseline

There is emerging evidence in schizophrenia of membrane abnormalities, primarily reductions in the essential omega-3 and omega-6 series of polyunsaturated fatty acids (PUFA). Because previous studies have largely been in chronic patients, it is not known whether these membrane abnormalities also occur early in illness. In the present study, red blood cell membrane fatty acid levels were determined by capillary gas chromatography from 24 neuroleptic-naive patients with first episode schizophrenia or schizoaffective disorder and 31 age-matched normal controls. Relative to normal subjects, patients had significant reductions in total PUFA (-13%) but not in monounsaturated or saturated fatty acids. Specifically, significant reductions were found in arachidonic acid (-18%), docosapentaenoic acid (-36%), and docosahexaenoic acid (-26%) concentrations. These reductions were not related to age, gender, smoking status, or cotinine levels. These results confirm previous findings of membrane deficits in schizophrenia and show that significant PUFA reductions occur early in the illness, prior to initiation of treatment, raising the possibility that these deficits are trait related. The findings also suggest that membrane fatty acid losses are quite specific to the highly unsaturated fatty acids.     

Increased breath ethane levels in medicated patients with schizophrenia and bipolar disorder are unrelated to erythrocyte omega-3 fatty acid abundance

Oxidative stress has been reported to be elevated in mental illness. Preliminary evidence suggests this phenomenon can be assessed non-invasively by determining breath levels of the omega-3 polyunsaturated fatty acid (PUFA) oxidation product ethane. This study compares alkane levels in chronic, medicated, patients with schizophrenia or bipolar disorder with those in healthy controls. Both ethane and butane levels were significantly increased in patients with schizophrenia or bipolar disorder, although elevated butane levels were likely due to increased ambient gas concentrations. Ethane levels were not correlated with symptom severity or with erythrocyte omega-3 PUFA levels. Our results support the hypothesis that oxidative stress is elevated in patients with schizophrenia and bipolar disorder leading to increased breath ethane abundance. This does not appear to be caused by increased abundance of omega-3 PUFA, but rather is likely due to enhanced oxidative damage of these lipids. As such, breath hydrocarbon analysis may represent a simple, non-invasive means to monitor the metabolic processes occurring in these disorders.     

Comparison of biochemical effects of statins and fish oil in brain: the battle of the titans

Neural membranes are composed of glycerophospholipids, sphingolipids, cholesterol and proteins. The distribution of these lipids within the neural membrane is not random but organized. Neural membranes contain lipid rafts or microdomains that are enriched in sphingolipids and cholesterol. These rafts act as platforms for the generation of glycerophospholipid-, sphingolipid-, and cholesterol-derived second messengers, lipid mediators that are necessary for normal cellular function. Glycerophospholipid-derived lipid mediators include eicosanoids, docosanoids, lipoxins, and platelet-activating factor. Sphingolipid-derived lipid mediators include ceramides, ceramide 1-phosphates, and sphingosine 1-phosphate. Cholesterol-derived lipid mediators include 24-hydroxycholesterol, 25-hydroxycholesterol, and 7-ketocholesterol. Abnormal signal transduction processes and enhanced production of lipid mediators cause oxidative stress and inflammation. These processes are closely associated with the pathogenesis of acute neural trauma (stroke, spinal cord injury, and head injury) and neurodegenerative diseases such as Alzheimer disease. Statins, the HMG-CoA reductase inhibitors, are effective lipid lowering agents that significantly reduce risk for cardiovascular and cerebrovascular diseases. Beneficial effects of statins in neurological diseases are due to their anti-excitotoxic, antioxidant, and anti-inflammatory properties. Fish oil omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have similar anti-excitotoxic, antioxidant and anti-inflammatory effects in brain tissue. Thus the lipid mediators, resolvins, protectins, and neuroprotectins, derived from eicosapentaenoic acid and docosahexaenoic acid retard neuroinflammation, oxidative stress, and apoptotic cell death in brain tissue. Like statins, ingredients of fish oil inhibit generation of beta-amyloid and provide protection from oxidative stress and inflammatory processes. Collective evidence suggests that antioxidant, anti-inflammatory, and anti-apoptotic properties of statins and fish oil contribute to the clinical efficacy of treating neurological disorders with statins and fish oil. We speculate that there is an overlap between neurochemical events associated with neural cell injury in stroke and neurodegenerative diseases. This commentary compares the neurochemical effects of statins with those of fish oil.     

Omega-3 Fatty Acids in Psychiatry: A Review

Omega-3 fatty acids are long-chain, polyunsaturated fatty acids found in plant and marine sources. Unlike saturated fats, which have been shown to have negative health consequences, omega-3 fatty acids are polyunsaturated fatty acids that have been associated with many health benefits. Omega-3 fatty acids may prove to be efficacious in a number of psychiatric disorders. Mood disorders have been associated with abnormalities in fatty acid composition. Several lines of evidence suggest that diminished omega-3 fatty acid concentrations are associated with mood disorders. Clinical data are not yet available regarding omega-3 fatty acids in the treatment of major depression. However, one double-blind treatment trial has been conducted in bipolar disorder. Also, substantial evidence does exist supporting a potential role of omega-3 fatty acids in schizophrenia, although treatment data are needed. A case has been reported in which a patient with schizophrenia was successfully treated with omega-3 fatty acids. Controlled studies are necessary to explore the potential treatment of schizophrenia with omega-3 fatty acids. Omega-3 fatty acids may also be helpful in the treatment of dementia. Furthermore, omega-3 fatty acids may prove to be a safe and efficacious treatment for psychiatric disorders in pregnancy and in breastfeeding.     

Qualitative analysis of hippocampal plastic changes in rats with epilepsy supplemented with oral omega-3 fatty acids

Studies have provided evidence of the important effects of omega-3 fatty acid on the brain in neurological conditions, including epilepsy. Previous data have indicated that omega-3 fatty acids lead to prevention of status epilepticus-associated neuropathological changes in the hippocampal formation of rats with epilepsy. Omega-3 fatty acid supplementation has resulted in extensive preservation of GABAergic cells in animals with epilepsy. This study investigated the interplay of these effects with neurogenesis and brain-derived neurotrophic factor (BDNF). The results clearly showed a positive effect of long-term omega-3 fatty acid supplementation on brain plasticity in animals with epilepsy. Enhanced hippocampal neurogenesis and BDNF levels and preservation of interneurons expressing parvalbumin were observed. Parvalbumin-positive cells were identified as surviving instead of newly formed cells. Additional investigations are needed to determine the electrophysiological properties of the newly formed cells and to clarify whether the effects of omega-3 fatty acids on brain plasticity are accompanied by functional gain in animals with epilepsy.     

Weight loss in neurodegenerative disorders

Unintended weight loss frequently complicates the course of many neurodegenerative disorders and can contribute substantially to both morbidity and mortality. This will be illustrated here by reviewing the characteristics of unintended weight loss in the three major neurodegenerative disorders: Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. A common denominator of weight loss in these neurodegenerative disorders is its typically complex pathophysiology. Timely recognition of the underlying pathophysiological process is of crucial importance, since a tailored treatment of weight loss can considerably improve the quality of life. This treatment is, primarily, comprised of a number of methods of increasing energy intake. Moreover, there are indications for defects in the systemic energy homeostasis and gastrointestinal function, which may also serve as therapeutic targets. However, the clinical merits of such interventions have yet to be demonstrated.     

Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders

Activation of glutamate receptors can trigger the death of neurons and some types of glial cells, particularly when the cells are coincidentally subjected to adverse conditions such as reduced levels of oxygen or glucose, increased levels of oxidative stress, exposure to toxins or other pathogenic agents, or a disease-causing genetic mutation. Such excitotoxic cell death involves excessive calcium influx and release from internal organelles, oxyradical production, and engagement of programmed cell death (apoptosis) cascades. Apoptotic proteins such as p53, Bax, and Par-4 induce mitochondrial membrane permeability changes resulting in the release of cytochrome c and the activation of proteases, such as caspase-3. Events occurring at several subcellular sites, including the plasma membrane, endoplasmic reticulum, mitochondria and nucleus play important roles in excitotoxicity. Excitotoxic cascades are initiated in postsynaptic dendrites and may either cause local degeneration or plasticity of those synapses, or may propagate the signals to the cell body resulting in cell death. Cells possess an array of anti-excitotoxic mechanisms including neurotrophic signaling pathways, intrinsic stress-response pathways, and survival proteins such as protein chaperones, calcium-binding proteins, and inhibitor of apoptosis proteins. Considerable evidence supports roles for excitotoxicity in acute disorders such as epileptic seizures, stroke and traumatic brain and spinal cord injury, as well as in chronic age-related disorders such as Alzheimer’s, Parkinson’s, and Huntington’s disease and amyotrophic lateral sclerosis. A better understanding of the excitotoxic process is not only leading to the development of novel therapeutic approaches for neurodegenerative disorders, but also to unexpected insight into mechanisms of synaptic plasticity.     

Insights into the inhibition of platelet activation by omega-3 polyunsaturated fatty acids: beyond aspirin and clopidogrel

Objectives

We sought to examine the effects of escalating doses of omega-3 polyunsaturated fatty acid (PUFA) supplements on platelet function using light transmission aggregometry (LTA) and electrophoretic quasi-elastic light scattering technology (EQELS).

Background

PUFA may inhibit platelet function through fatty acid substitution in the platelet membrane by changing the surface charge density and causing decreased production of thromboxane A2. EQELS can measure platelet surface charge density and determine whether the platelet is in resting or activated state.

Methods

A total of 30volunteers were divided in 3 groups of 10 as follows: Group A, no antiplatelet agent; Group B, daily aspirin only, and Group C, daily aspirin and clopidogrel. All patients received escalating doses of omega-3PUFA from 1 to 8 g daily over 24 weeks. Platelet function was measured by template bleeding time, LTA, and EQELS at baseline and at 6, 12, 18 and 24 weeks.

Results

Mean bleeding time increased in a dose-dependent manner with escalating omega-3 PUFA doses. LTA confirmed expected antiplatelet effects of aspirin and clopidogrel, but did not detect any additional antiplatelet effects of omega-3 PUFA. EQELS showed a significant increase in the negative resting platelet charge compared to baseline and an attenuated response to arachidonic acid mediated platelet activation. No bleeding events were observed.

Conclusions

In this pilot study we were able to successfully measure platelet surface charge variation as a measure of omega-3 PUFA effect on platelets. Our results suggest that omega-3 PUFA increase the total platelet surface charge and, therefore, attenuate platelet activation, even among patients taking aspirin or aspirin plus clopidogrel. Further studies are needed to determine the clinical significance of these measured effects and EQELS results.     

Role of omega-3 fatty acids as a treatment for depression in the perinatal period

OBJECTIVES: To consider the possible rationale and utility of omega-3 fatty acids as a treatment for depression in the perinatal period. METHOD: A review of published and unpublished research was undertaken, using electronic databases, conferences proceedings and expert informants. RESULTS: Relevant bodies of evidence include an epidemiological link between low fish intake and depression. Laboratory studies show correlations between low omega-3 fatty acid levels and depression, as well as reduced levels of omega-3 in non-depressed women during the perinatal period. Treatment studies using omega-3 in patients with mood disorders further support an omega-3 contribution, as do neuroscientific theories. Research into omega-3 and infant development also highlights potential effects of depletion in the perinatal period and supports infant safety and benefits of supplementation. CONCLUSIONS: There is a relative lack of knowledge about the safety of standard antidepressants in the perinatal period. There is a clear need for more research into alternative treatments, such as omega-3 fatty acids, in the management of depression in the perinatal period.     

Omega-6 and omega-3 fatty acids predict accelerated decline of peripheral nerve function in older persons

Pre-clinical studies suggest that both omega-6 and omega-3 fatty acids have beneficial effects on peripheral nerve function. Rats feed a diet rich in polyunsaturated fatty acids (PUFAs) showed modification of phospholipid fatty acid composition in nerve membranes and improvement of sciatic nerve conduction velocity (NCV). We tested the hypothesis that baseline plasma omega-6 and omega-3 fatty acids levels predict accelerated decline of peripheral nerve function. Changes between baseline and the 3-year follow-up in peripheral nerve function was assessed by standard surface ENG of the right peroneal nerve in 384 male and 443 female participants of the InCHIANTI study (age range: 24–97 years). Plasma concentrations of selected fatty acids assessed at baseline by gas chromatography. Independent of confounders, plasma omega-6 fatty acids and linoleic acid were significantly correlated with peroneal NCV at enrollment. Lower plasma PUFA, omega-6 fatty acids, linoleic acid, ratio omega-6/omega-3, arachidonic acid and docosahexanoic acid levels were significantly predicted a steeper decline in nerve function parameters over the 3-year follow-up. Low plasma omega-6 and omega-3 fatty acids levels were associated with accelerated decline of peripheral nerve function with aging.     

Childrens’ learning and behaviour and the association with cheek cell polyunsaturated fatty acid levels

Increasing interest in the role of omega-3 fatty acids in relation to neurodevelopmental disorders (e.g. ADHD, dyslexia, autism) has occurred as a consequence of some international studies highlighting this link. In particular, some studies have shown that children with ADHD may have lower concentrations of polyunsaturated fatty acids (PUFAs), particularly omega-3, in their red blood cells and plasma, and that supplementation with omega-3 fatty acids may alleviate behavioural symptoms in this population. However, in order to compare levels it seems appropriate to establish fatty acid levels in a mainstream school aged population and if levels relate to learning and behaviour. To date no study has established this. For this study, cheek cell samples from 411 typically developing school children were collected and analysed for PUFA content, in order to establish the range in this population. In addition, measures of general classroom attention and behaviour were assessed in these children by teachers and parents. Cognitive performance tests were also administered in order to explore whether an association between behaviour and/or cognitive performance and PUFA levels exists. Relationships between PUFA levels and socio-economic status were also explored. Measures of reading, spelling and intelligence did not show any association with PUFA levels, but some associations were noted with the level of omega-3 fatty acids and teacher and parental reports of behaviour, with some evidence that higher omega-3 levels were associated with decreased levels of inattention, hyperactivity, emotional and conduct difficulties and increased levels of prosocial behaviour. These findings are discussed in relation to previous findings from omega-3 supplementation studies with children.     

Membrane phospholipid composition, alterations in neurotransmitter systems and schizophrenia

This review addresses the relationship between modifications in membrane phospholipid composition (MPC) and alterations in dopaminergic, serotonergic and cholinergic neurotransmitter systems in schizophrenia. The main evidence in support of the MPC hypothesis of schizophrenia comes from post-mortem and platelet studies, which show that in schizophrenia, certain omega-3 and omega-6 polyunsaturated fatty acid (PUFA) levels are reduced. Furthermore, examination of several biochemical markers suggests abnormal fatty acid metabolism may be present in schizophrenia. Dietary manipulation of MPC with polyunsaturated fatty acid diets has been shown to affect densities of dopamine, serotonin and muscarinic receptors in rats. Also, supplementation with omega-3 fatty acids has been shown to improve mental health rating scores, and there is evidence that the mechanism behind this involves the serotonin receptor complex. This suggests that a tight relationship exists between essential fatty acid status and normal neurotransmission, and that altered PUFA levels may contribute to the abnormalities in neurotransmission seen in schizophrenia.     

Investigation of the effect of dietary intake of omega-3 polyunsaturated fatty acids on trauma-induced white matter injury with quantitative diffusion MRI in mice

Previous studies suggest that long-term supplementation and dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) may have neuroprotective effects following brain injury. The objective of this study was to investigate potential neuroprotective effects of omega-3 PUFAs on white matter following closed-head trauma. The closed-head injury model of engineered rotational acceleration (CHIMERA) produces a reproducible injury in the optic tract and brachium of the superior colliculus in mice. Damage is detectable using diffusion tensor imaging (DTI) metrics, particularly fractional anisotropy (FA), with sensitivity comparable to histology. We acquired in vivo (n = 38) and ex vivo (n = 41) DTI data in mice divided into sham and CHIMERA groups with two dietary groups: one deficient in omega-3 PUFAs and one adequate in omega-3 PUFAs. We examined injury effects (reduction in FA) and neuroprotection (FA reduction modulated by diet) in the optic tract and brachium. We verified that diet did not affect FA in sham animals. In injured animals, we found significantly reduced FA in the optic tract and brachium (~10% reduction, p < 0.001), and Bayes factor analysis showed strong evidence to reject the null hypothesis. However, Bayes factor analysis showed substantial evidence to accept the null hypothesis of no diet-related FA differences in injured animals in the in vivo and ex vivo samples. Our results indicate no neuroprotective effect from adequate dietary omega-3 PUFA intake on white matter damage following traumatic brain injury. Since damage from CHIMERA mainly affects white matter, our results do not necessarily contradict previous findings showing omega-3 PUFA-mediated neuroprotection in gray matter.     

Lipides membranaires dans la schizophrénie et la psychose débutante : de potentiels biomarqueurs et pistes thérapeutiques ?

The various roles of membrane lipids in human health has urged researchers to study their impact in neuropsychiatric diseases, especially in schizophrenia spectrum disorders and more recently in early stages of psychosis. The progress in mass spectrometry technologies now allows a more comprehensive analysis of phospholipids (PL) and their fatty acid (FA) molecular species. FA are defined by a carbon chain of variable length and are said to be unsaturated when their chain has one or more carbon-carbon double bonds. The PL are composed of a hydrophilic polar head with a phosphoric acid group and an hydrophobic part with FAs; they encompass glycerophospholipids and sphingolipids. The plasma membrane is a complex and dynamic structure consisting of a lipid bilayer composed of an outer layer and an inner layer of specific lipid composition. The permanent remodeling of membrane lipids involves phospholipases especially the phospholipase A2. Seventy percent of the brain consists of lipids from different classes and molecular species. Most of the brain lipids are composed of polyunsaturated fatty acid (PUFA)-enriched diacyl classes where omega-3 and omega-6 molecular species predominate. The balance between omega-3 and omega-6 is important for the neurodevelopment. PUFA are also involved in neurogenesis and neurotransmission. Sphingomyelin (SM) is a sphingolipid that influences inflammation, cell proliferation and lipid rafts formation. It is an important component of myelin sheaths of white matter and therefore is involved in cerebral connectivity. In rat models, deficiency in omega-3 causes abnormalities in dopaminergic neurotransmission, impacts on the functioning of some receptors (including cannabinoids CB1, glutamatergic N-methyl-D-aspartate receptor, NMDA), and increases sensitivity to hallucinogens. In contrast, omega-3 supplementation improves cognitive function and prevents psychotic-like behavior in some animal models for schizophrenia. It also reduces oxidative stress and prevents demyelination. The historical membrane hypothesis of schizophrenia has led to explore the lipids abnormality in this disorder. This hypothesis was initially based on the observation of an abnormal membrane prostaglandin production in schizophrenia caused by a membrane arachidonic acid deficiency. It has evolved emphasizing the various PUFA membrane's roles in particular regarding oxidative stress, inflammation and regulation of the NMDA receptors. In patients with mental disorders, low omega-3 index is more frequent than in the general population. This lipid abnormality could lead to myelination abnormalities and cognitive deficits observed in patients. It could also participate in oxidative stress abnormalities and inflammation reported in schizophrenia. On the other hand, low omega-3 index deficit was reported to be associated with an increased cardiovascular risk, and omega-3 supplementation may also have a positive cardiovascular impact in psychiatric patients, even more than in the general population. The presence of membrane lipid abnormalities is also found in patients during the first psychotic episode (FEP). The omega-3 supplementation improved the recovery rate and prevented the loss of gray matter in FEP. In patients at ultra-high risk to develop a psychotic disorder (UHR), omega-3 supplementation has been associated with a reduction of the rate of conversion to psychosis and with metabolic changes, such as decreased activity of phospholipase A2. However, this study has not as yet been replicated. Not all patients exhibit lipid abnormalities. Several studies, including studies from our team, have found a bimodal distribution of lipids in patients with schizophrenia. But some studies have found differences (in PUFA) in the acute phase whereas our studies (on phospholipids) are in chronic phases. It will be interesting to study in more depth the links between these two parameters. Furthermore, we identified a subgroup which was identified with a deficit in sphingomyelin and PUFA whereas others have found an increase of sphingomyelin. Individuals with this abnormal lipid cluster had more cognitive impairments and more severe clinical symptoms. Because the niacin test is an indirect reflection of arachidonic acid levels, it has been proposed to identify a subset of patients with membrane lipids anomalies. Niacin test response is influenced by several factors related to lipid metabolism, including cannabis use and phospholipase A2 activity. Despite progress, the function and impact of membrane lipids are still poorly understood in schizophrenia. They could serve as biomarkers for identifying biological subgroups among patients with schizophrenia. In UHR patients, their predictive value on the conversion to psychosis should be tested. Omega-3 supplementation could be a promising treatment thanks to its good tolerance and acceptability. It could be more appropriate for patients with PUFA anomalies in a more personalized medical approach.