Meta-analysis of synaptic pathology in Alzheimer's disease reveals selective molecular vesicular machinery vulnerability

AbstractIntroductionLoss of synapses best correlates to cognitive deficits in Alzheimer's disease (AD) in which oligomeric neurotoxic species of amyloid-β appears to contribute synaptic pathology. Although a number of clinical pathologic studies have been performed with limited sample size, there are no systematic studies encompassing large samples. Therefore, we performed a meta-analysis study.MethodsWe identified 417 publications reporting postmortem synapse and synaptic marker loss from AD patients. Two meta-analyses were performed using a single database of subselected publications and calculating the standard mean differences.ResultsMeta-analysis confirmed synaptic loss in selected brain regions is an early event in AD pathogenesis. The second meta-analysis of 57 synaptic markers revealed that presynaptic makers were affected more than postsynaptic markers.DiscussionThe present meta-analysis study showed a consistent synaptic loss across brain regions and that molecular machinery including endosomal pathways, vesicular assembly mechanisms, glutamate receptors, and axonal transport are often affected

Dietary Crude Lecithin Increases Systemic Availability of Dietary Docosahexaenoic Acid with Combined Intake in Rats

Crude lecithin, a mixture of mainly phospholipids, potentially helps to increase the systemic availability of dietary omega-3 polyunsaturated fatty acids (n-3 PUFA), such as docosahexaenoic acid (DHA). Nevertheless, no clear data exist on the effects of prolonged combined dietary supplementation of DHA and lecithin on RBC and plasma PUFA levels. In the current experiments, levels of DHA and choline, two dietary ingredients that enhance neuronal membrane formation and function, were determined in plasma and red blood cells (RBC) from rats after dietary supplementation of DHA-containing oils with and without concomitant dietary supplementation of crude lecithin for 2–3 weeks. The aim was to provide experimental evidence for the hypothesized additive effects of dietary lecithin (not containing any DHA) on top of dietary DHA on PUFA levels in plasma and RBC. Dietary supplementation of DHA-containing oils, either as vegetable algae oil or as fish oil, increased DHA, eicosapentaenoic acid (EPA), and total n-3 PUFA, and decreased total omega-6 PUFA levels in plasma and RBC, while dietary lecithin supplementation alone did not affect these levels. However, combined dietary supplementation of DHA and lecithin increased the changes induced by DHA supplementation alone. Animals receiving a lecithin-containing diet also had a higher plasma free choline concentration as compared to controls. In conclusion, dietary DHA-containing oils and crude lecithin have synergistic effects on increasing plasma and RBC n-3 PUFA levels, including DHA and EPA. By increasing the systemic availability of dietary DHA, dietary lecithin may increase the efficacy of DHA supplementation when their intake is combined.Nutricia Researc

Brain imaging and human nutrition: which measures to use in intervention studies?

The present review describes brain imaging technologies that can be used to assess the effects of nutritional interventions in human subjects. Specifically, we summarise the biological relevance of their outcome measures, practical use and feasibility, and recommended use in short- and long-term nutritional studies. The brain imaging technologies described consist of MRI, including diffusion tensor imaging, magnetic resonance spectroscopy and functional MRI, as well as electroencephalography/magnetoencephalography, near-IR spectroscopy, positron emission tomography and single-photon emission computerised tomography. In nutritional interventions and across the lifespan, brain imaging can detect macro- and microstructural, functional, electrophysiological and metabolic changes linked to broader functional outcomes, such as cognition. Imaging markers can be considered as specific for one or several brain processes and as surrogate instrumental endpoints that may provide sensitive measures of short- and long-term effects. For the majority of imaging measures, little information is available regarding their correlation with functional endpoints in healthy subjects; therefore, imaging markers generally cannot replace clinical endpoints that reflect the overall capacity of the brain to behaviourally respond to specific situations and stimuli. The principal added value of brain imaging measures for human nutritional intervention studies is their ability to provide unique in vivo information on the working mechanism of an intervention in hypothesis-driven research. Selection of brain imaging techniques and target markers within a given technique should mainly depend on the hypothesis regarding the mechanism of action of the intervention, level (structural, metabolic or functional) and anticipated timescale of the intervention's effects, target population, availability and costs of the technique

Dietary Crude Lecithin Increases Systemic Availability of Dietary Docosahexaenoic Acid with Combined Intake in Rats

Crude lecithin, a mixture of mainly phospholipids, potentially helps to increase the systemic availability of dietary omega-3 polyunsaturated fatty acids (n-3 PUFA), such as docosahexaenoic acid (DHA). Nevertheless, no clear data exist on the effects of prolonged combined dietary supplementation of DHA and lecithin on RBC and plasma PUFA levels. In the current experiments, levels of DHA and choline, two dietary ingredients that enhance neuronal membrane formation and function, were determined in plasma and red blood cells (RBC) from rats after dietary supplementation of DHA-containing oils with and without concomitant dietary supplementation of crude lecithin for 2–3 weeks. The aim was to provide experimental evidence for the hypothesized additive effects of dietary lecithin (not containing any DHA) on top of dietary DHA on PUFA levels in plasma and RBC. Dietary supplementation of DHA-containing oils, either as vegetable algae oil or as fish oil, increased DHA, eicosapentaenoic acid (EPA), and total n-3 PUFA, and decreased total omega-6 PUFA levels in plasma and RBC, while dietary lecithin supplementation alone did not affect these levels. However, combined dietary supplementation of DHA and lecithin increased the changes induced by DHA supplementation alone. Animals receiving a lecithin-containing diet also had a higher plasma free choline concentration as compared to controls. In conclusion, dietary DHA-containing oils and crude lecithin have synergistic effects on increasing plasma and RBC n-3 PUFA levels, including DHA and EPA. By increasing the systemic availability of dietary DHA, dietary lecithin may increase the efficacy of DHA supplementation when their intake is combined.Nutricia Researc

A Nutritional Approach to Ameliorate Altered Phospholipid Metabolism in Alzheimer's Disease

Abstract. Recently, a biomarker panel of 10 plasma lipids, including 8 phosphatidylcholine species, was identified that could predict phenoconversion from cognitive normal aged adults to amnestic mild cognitive impairment or Alzheimer's disease (AD) within 2-3 years with >90% accuracy. The reduced levels of these plasma phospholipids could reflect altered phospholipid metabolism in the brain and periphery. We show that a 24-week nutritional intervention in drug-naïve patients with very mild to mild AD significantly increased 5 of the 7 measured biomarker phosphatidylcholine species. By providing nutrients which normally rate-limit phospholipid synthesis, this nutritional intervention could be useful in asymptomatic subjects with a plasma lipid biomarker profile prognostic of AD

The medical food Souvenaid affects brain phospholipid metabolism in mild Alzheimer’s disease: results from a randomized controlled trial

Abstract Background Synaptic dysfunction contributes to cognitive impairment in Alzheimer’s disease and may be countered by increased intake of nutrients that target brain phospholipid metabolism. In this study, we explored whether the medical food Souvenaid affects brain phospholipid metabolism in patients with Alzheimer’s disease. Methods Thirty-four drug-naive patients with mild Alzheimer’s disease (Mini Mental State Examination score ≥20) were enrolled in this exploratory, double-blind, randomized controlled study. Before and after 4-week intervention with Souvenaid or an isocaloric control product, phosphorus and proton magnetic resonance spectroscopy (MRS) was performed to assess surrogate measures of phospholipid synthesis and breakdown (phosphomonoesters [PME] and phosphodiesters [PDEs]), neural integrity (N-acetyl aspartate), gliosis (myo-inositol), and choline metabolism (choline-containing compounds [tCho]). The main outcome parameters were PME and PDE signal intensities and the PME/PDE ratio. Results MRS data from 33 patients (60–86 years old; 42% males; Souvenaid arm n = 16; control arm n = 17) were analyzed. PME/PDE and tCho were higher after 4 weeks of Souvenaid compared with control (PME/PDE least squares [LS] mean difference [95% CI] 0.18 [0.06–0.30], p = 0.005; tCho LS mean difference [95% CI] 0.01 [0.00–0.02], p = 0.019). No significant differences were observed in the other MRS outcome parameters. Conclusions MRS reveals that Souvenaid affects brain phospholipid metabolism in mild Alzheimer’s disease, in line with findings in preclinical studies. Trial registration Netherlands Trial Register, NTR3346 . Registered on 13 March 2012

Combined dietary folate, vitamin B-12, and vitamin B-6 intake influences plasma docosahexaenoic acid concentration in rats

<p>Abstract</p> <p>Background</p> <p>Folate, vitamin B-12, and vitamin B-6 are essential nutritional components in one-carbon metabolism and are required for methylation capacity. The availability of these vitamins may therefore modify methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) by PE-<it>N</it>-methyltransferase (PEMT) in the liver. It has been suggested that PC synthesis by PEMT plays an important role in the transport of polyunsaturated fatty acids (PUFAs) like docosahexaenoic acid (DHA) from the liver to plasma and possibly other tissues. We hypothesized that if B-vitamin supplementation enhances PEMT activity, then supplementation could also increase the concentration of plasma levels of PUFAs such as DHA. To test this hypothesis, we determined the effect of varying the combined dietary intake of these three B-vitamins on plasma DHA concentration in rats.</p> <p>Methods</p> <p>In a first experiment, plasma DHA and plasma homocysteine concentrations were measured in rats that had consumed a B-vitamin-poor diet for 4 weeks after which they were either continued on the B-vitamin-poor diet or switched to a B-vitamin-enriched diet for another 4 weeks. In a second experiment, plasma DHA and plasma homocysteine concentrations were measured in rats after feeding them one of four diets with varying levels of B-vitamins for 4 weeks. The diets provided 0% (poor), 100% (normal), 400% (enriched), and 1600% (high) of the laboratory rodent requirements for each of the three B-vitamins.</p> <p>Results</p> <p>Plasma DHA concentration was higher in rats fed the B-vitamin-enriched diet than in rats that were continued on the B-vitamin-poor diet (<it>P</it> = 0.005; experiment A). Varying dietary B-vitamin intake from deficient to supra-physiologic resulted in a non-linear dose-dependent trend for increasing plasma DHA (<it>P</it> = 0.027; experiment B). Plasma DHA was lowest in rats consuming the B-vitamin-poor diet (<it>P</it> > 0.05 vs<it>.</it> normal, <it>P</it> < 0.05 vs<it>.</it> enriched and high) and highest in rats consuming the B-vitamin-high diet (<it>P</it> < 0.05 vs<it>.</it> poor and normal, <it>P</it> > 0.05 vs<it>.</it> enriched). B-vitamin deficiency significantly increased plasma total homocysteine but increasing intake above normal did not significantly reduce it. Nevertheless, in both experiments plasma DHA was inversely correlated with plasma total homocysteine.</p> <p>Conclusion</p> <p>These data demonstrate that dietary folate, vitamin B-12, and vitamin B-6 intake can influence plasma concentration of DHA.</p

Differential immunomodulation with long-chain n-3 PUFA in health and chronic disease

The balance of intake of n-6 and n-3 PUFA, and consequently their relative incorporation into immune cells, is important in determining the development and severity of immune and inflammatory responses. Some disorders characterised by exaggerated inflammation and excessive formation of inflammatory markers have become among the most important causes of death and disability in man in modern societies. The recognition that long-chain n-3 PUFA have the potential to inhibit (excessive) inflammatory responses has led to a large number of clinical investigations with these fatty acids in inflammatory conditions as well as in healthy subjects. The present review explores the presence of dose-related effects of long-chain n-3 PUFA supplementation on immune markers and differences between healthy subjects and those with inflammatory conditions, because of the important implications for the transfer of information gained from studies with healthy subjects to patient populations, e.g. for establishing dose levels for specific applications. The effects of long-chain n-3 PUFA supplementation on ex vivo lymphocyte proliferation and cytokine production by lymphocytes and monocytes in healthy subjects have been studied in twenty-seven, twenty-five and forty-six treatment cohorts respectively, at intake levels ranging from 0.2 g EPA+DHA/d to 7.0 g EPA+DHA/d. Most studies, particularly those with the highest quality study design, have found no effects on these immune markers. Significant effects on lymphocyte proliferation are decreased responses in seven of eight cohorts, particularly in older subjects. The direction of the significant changes in cytokine production by lymphocytes is inconsistent and only found at supplementation levels &gt; or =2.0 g EPA+DHA/d. Significant changes in inflammatory cytokine production by monocytes are decreases in their production in all instances. Overall, these studies fail to reveal strong dose-response effects of EPA+DHA on the outcomes measured and suggest that healthy subjects are relatively insensitive to immunomodulation with long-chain n-3 PUFA, even at intake levels that substantially raise their concentrations in phospholipids of immune cells. In patients with inflammatory conditions cytokine concentrations or production are influenced by EPA+DHA supplementation in a relatively large number of studies. Some of these studies suggest that local effects at the site of inflammation might be more pronounced than systemic effects and disease-related markers are more sensitive to the immunomodulatory effects, indicating that the presence of inflamed tissue or 'sensitised' immune cells in inflammatory disorders might increase sensitivity to the immunomodulatory effects of long-chain n-3 PUFA. In a substantial number of these studies clinical benefits related to the inflammatory state of the condition have been observed in the absence of significant effects on immune markers of inflammation. This finding suggests that condition-specific clinical end points might be more sensitive markers of modulation by EPA+DHA than cytokines. In general, the direction of immunomodulation in healthy subjects (if any) and in inflammatory conditions is the same, which indicates that studies in healthy subjects are a useful tool to describe the general principles of immunomodulation by n-3 PUFA. However, the extent of the effect might be very different in inflammatory conditions, indicating that studies in healthy subjects are not particularly suitable for establishing dose levels for specific applications in inflammatory conditions. The reviewed studies provide no indications that the immunomodulatory effects of long-chain n-3 PUFA impair immune function or infectious disease resistance. In contrast, in some conditions the immunomodulatory effects of EPA+DHA might improve immune function

Nutrients required for phospholipid synthesis are lower in blood and cerebrospinal fluid in mild cognitive impairment and Alzheimer's disease dementia

Introduction Synaptic membrane formation depends on nutrients that fuel metabolic pathways for the synthesis of constituent phospholipids. Consequently, insufficient availability of such nutrients may restrict membrane formation and contribute to synaptic dysfunction in Alzheimer's disease (AD). We assessed whether blood and cerebrospinal fluid (CSF) concentrations of nutrients related to phospholipid synthesis differ among patients with AD, mild cognitive impairment (MCI), and control subjects. Methods Concentrations of uridine, choline, folate, homocysteine, and other related metabolites were analyzed in paired blood and CSF samples from subjects selected from the Amsterdam Dementia Cohort with AD (n = 150; age, 66 ± 7 years; 37% female), MCI (n = 148; age, 66 ± 8 years; 37% female), and control subjects (n = 148; age, 59 ± 8 years; 38% female). Results Age- and gender-adjusted analysis of variance revealed different concentrations of circulating uridine, choline, and folate and CSF uridine, folate, and homocysteine (all P <.05) among the three diagnostic groups. Post hoc pairwise comparison showed that subjects with AD had lower CSF uridine, plasma choline and higher CSF homocysteine concentrations, whereas subjects with MCI had lower plasma and CSF uridine, serum and CSF folate, and higher CSF homocysteine concentrations compared with control subjects (all P <.05), with differences ranging from −11 to +22%. Discussion AD and MCI patients have lower levels of nutrients involved in phospholipid synthesis. The current observations warrant exploration of the application of nutritional strategies in the early stages of AD

Differences in Nutritional Status Between Very Mild Alzheimer's Disease Patients and Healthy Controls

Background: Studies on the systemic availability of nutrients and nutritional status in Alzheimer's disease (AD) are widely available, but the majority included patients in a moderate stage of AD. Objective: This study compares the nutritional status between mild AD outpatients and healthy controls. Methods: A subgroup of Dutch drug-naive patients with mild AD (Mini-Mental State Examination (MMSE) &gt;= 20) from the Souvenir II randomized controlled study (NTR1975) and a group of Dutch healthy controls were included. Nutritional status was assessed by measuring levels of several nutrients, conducting the Mini Nutritional Assessment (MNA (R)) questionnaire and through anthropometric measures. Results: In total, data of 93 healthy cognitively intact controls (MMSE 29.0 [23.0-30.0]) and 79 very mild AD patients (MMSE = 25.0 [20.0-30.0]) were included. Plasma selenium (p &lt;0.001) and uridine (p = 0.046) levels were significantly lower in AD patients, with a similar trend for plasma vitamin D (p = 0.094) levels. In addition, the fatty acid profile in erythrocyte membranes was different between groups for several fatty acids. Mean MNA screening score was significantly lower in AD patients (p = 0.008), but not indicative of malnutrition risk. No significant differences were observed for other micronutrient or anthropometric parameters. Conclusion: In non-malnourished patients with very mild AD, lower levels of some micronutrients, a different fatty acid profile in erythrocyte membranes and a slightly but significantly lower MNA screening score were observed. This suggests that subtle differences in nutrient status are present already in a very early stage of AD and in the absence of protein/energy malnutrition