Exploratory study of the effect of brain tumors on the default mode network.

Resting state functional magnetic resonance imaging (RS-fMRI) is a popular method of visualizing functional networks in the brain. One of these networks, the default mode network (DMN), has exhibited altered connectivity in a variety of pathological states, including brain tumors. However, very few studies have attempted to link the effect of tumor localization, type and size on DMN connectivity. We collected RS-fMRI data in 73 patients with various brain tumors and attempted to characterize the different effects these tumors had on DMN connectivity based on their location, type and size. This was done by comparing the tumor patients with healthy controls using independent component analysis (ICA) and seed based analysis. We also used a multi-seed approach described in the paper to account for anatomy distortion in the tumor patients. We found that tumors in the left hemisphere had the largest effect on DMN connectivity regardless of their size and type, while this effect was not observed for right hemispheric tumors. Tumors in the cerebellum also had statistically significant effects on DMN connectivity. These results suggest that DMN connectivity in the left side of the brain may be more fragile to insults by lesions.

Relationship of metabolic and endocrine parameters to brain glucose metabolism in older adults: do cognitively-normal older adults have a particular metabolic phenotype?

Our primary objective in this study was to quantify whole brain and regional cerebral metabolic rates of glucose (CMRg) in young and older adults in order to determine age-normalized reference CMRg values for healthy older adults with normal cognition for age. Our secondary objectives were to--(i) report a broader range of metabolic and endocrine parameters including body fat composition that could form the basis for the concept of a 'metabolic phenotype' in cognitively normal, older adults, and (ii) to assess whether medications commonly used to control blood lipids, blood pressure or thyroxine affect CMRg values in older adults. Cognition assessed by a battery of tests was normal for age and education in both groups. Compared to the young group (25 years old; n = 34), the older group (72 years old; n = 41) had ~14% lower CMRg (µmol/100 g/min) specifically in the frontal cortex, and 18% lower CMRg in the caudate. Lower grey matter volume and cortical thickness was widespread in the older group. These differences in CMRg, grey matter volume and cortical thickness were present in the absence of any known evidence for prodromal Alzheimer's disease (AD). Percent total body fat was positively correlated with CMRg in many brain regions but only in the older group. Before and after controlling for body fat, HOMA2-IR was significantly positively correlated to CMRg in several brain regions in the older group. These data show that compared to a healthy younger adult, the metabolic phenotype of a cognitively-normal 72 year old person includes similar plasma glucose, insulin, cholesterol, triglycerides and TSH, higher hemoglobin A1c and percent body fat, lower CMRg in the superior frontal cortex and caudate, but the same CMRg in the hippocampus and white matter. Age-normalization of cognitive test results is standard practice and we would suggest that regional CMRg in cognitively healthy older adults should also be age-normalized.

Disturbance in uniformly 13C-labelled DHA metabolism in elderly human subjects carrying the apoE ε4 allele.

Carrying the apoE ε4 allele (E4+ ) is the most important genetic risk for Alzheimer's disease. Unlike non-carriers (E4- ), E4+ seem not to be protected against Alzheimer's disease when consuming fish. We hypothesised that this may be linked to a disturbance in n-3 DHA metabolism in E4+. The aim of the present study was to evaluate [13C]DHA metabolism over 28 d in E4+ v. E4-. A total of forty participants (twenty-six women and fourteen men) received a single oral dose of 40 mg [13C]DHA, and its metabolism was monitored in blood and breath over 28 d. Of the participants, six were E4+ and thirty-four were E4-. In E4+, mean plasma [13C]DHA was 31% lower than that in E4-, and cumulative b-oxidation of [13C]DHA was higher than that in E4- 1­28 d post-dose (P ≤0·05). A genotype x time interaction was detected for cumulative b-oxidation of [13C]DHA (P ≤ 0·01). The whole-body half-life of [13C]DHA was 77% lower in E4+ compared with E4- (P ≤0·01). In E4+ and E4-, the percentage dose of [13C]DHA recovered/h as 13CO2 correlated with [13C]DHA concentration in plasma, but the slope of linear regression was 117% steeper in E4+ compared with E4- (P ≤ 0·05). These results indicate that DHA metabolism is disturbed in E4+, and may help explain why there is no association between DHA levels in plasma and cognition in E4+. However, whether E4+ disturbs the metabolism of 13C-labelled fatty acids other than DHA cannot be deduced from the present study.

Metabolic response to a ketogenic breakfast in the healthy elderly.

OBJECTIVE: To determine whether the metabolism of glucose or ketones differs in the healthy elderly compared to young or middle-aged adults during mild, short-term ketosis induced by a ketogenic breakfast. DESIGN AND PARTICIPANTS: Healthy subjects in three age groups (23 +/- 1, 50 +/- 1 and 76 +/- 2 y old) were given a ketogenic meal and plasma beta -hydroxybutyrate, glucose, insulin, triacylglycerols, total cholesterol, non-esterified fatty acids and breath acetone were measured over the subsequent 6 h. Each subject completed the protocol twice in order to determine the oxidation of a tracer dose of both carbon-13 (13C) glucose and 13C-beta-hydroxybutyrate. The tracers were given separately in random order. Apolipoprotein E genotype was also determined in all subjects. RESULTS: Plasma glucose decreased and beta-hydroxybutyrate, acetone and insulin increased similarly over 6 h in all three groups after the ketogenic meal. There was no significant change in cholesterol, triacylglycerols or non-esterified fatty acids over the 6 h. 13C-glucose and 13C-beta-hydroxybutyrate oxidation peaked at 2-3 h postdose for all age groups. Cumulative 13C-glucose oxidation over 24 h was significantly higher in the elderly but only versus the middle-aged group. There was no difference in cumulative 13C-beta-hydroxybutyrate oxidation between the three groups. Apolipoprotein E (epsilon 4) was associated with elevated fasting cholesterol but was unrelated to the other plasma metabolites. CONCLUSION: Elderly people in relatively good health have a similar capacity to produce ketones and to oxidize 13C-beta-hydroxybutyrate as middle-aged or young adults, but oxidize 13C-glucose a little more rapidly than healthy middle-aged adults.

Impaired plasma nonesterified fatty acid tolerance is an early defect in the natural history of type 2 diabetes.

CONTEXT: Abnormal plasma nonesterified fatty acid (NEFA) metabolism may play a role in the development of type 2 diabetes. OBJECTIVES: Our objectives were to demonstrate whether there is a defect in insulin-mediated suppression of plasma NEFA appearance (RaNEFA) and oxidation (OxNEFA) during enhanced intravascular triacylglycerol lipolysis early in the natural history of type 2 diabetes, and if so, to determine whether other mechanisms than reduced insulin-mediated suppression of intracellular lipolysis are involved. DESIGN: These are cross-sectional studies. SETTING: The studies were performed at an academic clinical research center. PARTICIPANTS: Nine healthy subjects with both parents with type 2 diabetes (FH+) and nine healthy subjects with no first-degree relatives with type 2 diabetes (FH-) with similar anthropometric features were included in the studies. INTERVENTIONS: Pancreatic clamps and iv infusion of stable isotopic tracers ([1,1,2,3,3-(2)H5]-glycerol and [U-(13)C]-palmitate or [1,2-(13)C]-acetate) were performed while intravascular triacylglycerol lipolysis was simultaneously clamped by iv infusion of heparin plus Intralipid at low (fasting) and high insulin levels. Oral nicotinic acid (NA) was used to inhibit intracellular lipolysis. MAIN OUTCOME MEASURES: RaNEFA and OxNEFA were determined. RESULTS: During heparin plus Intralipid infusion at high plasma insulin levels, and despite similar intravascular lipolytic rates, FH+ had higher RaNEFA and OxNEFA than FH- (RaNEFA: 17.4+/-6.3 vs. 9.2+/-4.2; OxNEFA: 4.5+/-1.8 vs. 2.3+/-1.5 micromol/kg lean body mass/min), independent of NA intake, gender, age, and body composition. In the presence of NA, insulin-mediated suppression of RaNEFA was still observed in FH-, but not in FH+. CONCLUSIONS: Increased RaNEFA and OxNEFA during intravascular lipolysis at high insulin levels occur early in the natural history of type 2 diabetes.

A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer's disease.

INTRODUCTION: Deteriorating brain glucose metabolism precedes the clinical onset of Alzheimer's disease (AD) and appears to contribute to its etiology. Ketone bodies, mainly ß-hydroxybutyrate and acetoacetate, are the primary alternative brain fuel to glucose. Some reports suggest that brain ketone metabolism is unchanged in AD but, to our knowledge, no such data are available for MCI. OBJECTIVE: To compare brain energy metabolism (glucose and acetoacetate) and some brain morphological characteristics in cognitively healthy older adult controls (CTL), mild cognitive impairment (MCI) and early AD. METHODS: 24 CTL, 20 MCI and 19AD of similar age and metabolic phenotype underwent a dual-tracer PET and MRI protocol. The uptake rate constants and cerebral metabolic rate of glucose (KGlu, CMRGlu) and acetoacetate (KAcAc, CMRAcAc) were evaluated with PET using [18F]-fluorodeoxyglucose ([18F]-FDG), a glucose analogue, and [11C]-acetoacetate ([11C]-AcAc), a ketone PET tracer. Regional brain volume and cortical thickness were evaluated by T1-weighted MRI. RESULTS: In AD compared to CTL, CMRGlu was ~11% lower in the frontal, parietal, temporal lobes and in the cingulate gyrus (p<0.05). KGlu was ~15% lower in these same regions and also in subcortical regions. In MCI compared to CTL, ~7% glucose hypometabolism was present in the cingulate gyrus. Neither regional nor whole brain CMRAcAc or KAcAc were significantly different between CTL and MCI or AD. Reduced gray matter volume and cortical thinning were widespread in AD compared to CTL, whereas, in MCI compared to CTL, volumes were reduced only in the temporal cortex and cortical thinning was most apparent in temporal and cingulate regions. DISCUSSION: This quantitative kinetic PET and MRI imaging protocol for brain glucose and acetoacetate metabolism confirms that the brain undergoes structural atrophy and lower brain energy metabolism in MCI and AD and demonstrates that the deterioration in brain energy metabolism is specific to glucose. These results suggest that a ketogenic intervention to increase energy availability for the brain is warranted in an attempt to delay further cognitive decline by compensating for the brain glucose deficit in MCI and AD.

Differential utilization of long chain fatty acids during fasting-induced triacylglycerol depletion. III. Comparison of n-3 and n-6 fatty acids in rat plasma and liver.

Previous research has shown that arachidonic acid (20:4(n-6)) is preferentially retained in liver triacylglycerol in fasted compared to fed rats consuming a diet containing n-6 fatty acids. It was hypothesized that eicosapentaenoic (20:5(n-3)) and docosahexaneoic acids (22:6(n-3)) would be similarly retained in liver and plasma triacylglycerol of fasted rats consuming a diet containing n-3 fatty acids. In comparison with fed rats, it was observed that in partially fasted rats consuming diets which contained 5% sunflower oil (78% 18:2(n-6)) or 5% marine fish oil (30% 20:5(n-3) and 22:6(n-3)), both liver and plasma had significantly depleted triacylglycerol levels containing higher proportions of both arachidonic and docosahexaneoic acids but a lower proportion of eicosapentaenoic acid (marine fish oil group only). Separation of liver and plasma triacylglycerol by silicic acid column chromatography and silver nitrate TLC showed that the majority of long chain fatty acids utilized during fasting were derived from the triacylglycerol subclasses containing palmitic acid (16:0), palmitoleic acid (16:1(n-7)) and oleic acid (18:1(n-9)) with retention o both highly saturated and polyunsaturated subclasses. Greater utilization of eicosapentaenoic acid than either arachidonic acid or docosahexaenoic acid during fasting may be due to triacylglycerol speciation of the former with readily oxidized monounsaturated fatty acids.

Fasting/refeeding has little lasting effect on long-chain fatty acids accumulating in the developing rat conceptus.

The objective of this study was to delineate the influence of maternal fasting-refeeding on accumulation of long-chain fatty acids by the developing conceptus in chow-fed pregnant rats. At term, the rat conceptus normally accumulates < 5% of total maternal whole body n - 6 polyunsaturates and < 15% of whole body n - 3 polyunsaturates. In contrast to the ad libitum-fed controls, the conceptus of fasted-refed rats was the main site of accumulation of n - 6 and n - 3 polyunsaturates since the maternal carcass (excluding liver) actually had a lower content of polyunsaturates at the end of the fasting-refeeding period than at the start. The rise in the content of triacylglycerols in the conceptus during fasting was specifically attributable to increased arachidonate, docosatetraenoate and docosahexaenoate; all changes in conceptus triacylglycerols were back to ad libitum control values by the end of the refeeding period (term). Conversely, although conceptus total phospholipids did not change significantly during fasting-refeeding, there was a net increase in the phospholipid content of both palmitate and oleate in conceptus after refeeding. We conclude that the developing rat conceptus is largely resistant to the marked changes in maternal fatty acid intake and retention that occur during fasting and refeeding.

Gestational hyperlipidemia in the rat is characterized by accumulation of n - 6 and n - 3 fatty acids, especially docosahexaenoic acid.

We have evaluated the relative and quantitative changes in long-chain fatty acids in maternal liver, serum, carcass and conceptus (fetuses plus placentae) during pregnancy in the rat, to ascertain whether previous concern over lower proportions of n - 6 and n - 3 fatty acids in maternal serum could be indicative of suboptimal n - 6 or n - 3 fatty acid status. Gestational hyperlipidemia was characterized by proportional decreases in linoleic, stearic and arachidonic acids but increases in palmitic and docosahexaenoic acids. However, the quantitative amount (microgram/ml) of linoleic, arachidonic and docosahexaenoic acids in serum lipids actually increased 2-5-fold from mid-pregnancy to term. Compared to non-pregnant rats, gestational hyperlipidemia was also associated with a lower proportion but similar quantity of linoleic acid in maternal carcass and adipose stores. We conclude that gestational hyperlipidemia in the rat is characterized by a relative but not quantitative decrease in whole-body stores of n - 6 fatty acids and a marked proportional and quantitative increase in docosahexaenoic acid in maternal organs and in the conceptus.

Triacylglycerol content of arachidonic acid varies inversely with total triacylglycerol in liver and plasma.

In both liver and plasma from rats, hamsters, guinea pigs and monkeys, the correlation coefficients between percentage composition of arachidonic acid and the total triacylglycerol varied from -0.43 to -0.81 (P less than 0.01). No such relationship was present between percentage compositions of any of the essential fatty acids in phospholipids and total phospholipids.

Metabolic effects of reducing rate of glucose ingestion by single bolus versus continuous sipping.

Modifying the rate of absorption has been proposed as a therapeutic principle of specific relevance to diabetes. To demonstrate clearly the metabolic benefits that might result from reducing the rate of nutrient delivery, nine healthy volunteers took 50 g glucose in 700 ml water on two occasions: over 5-10 min (bolus) and at a constant rate over 3.5 h (sipping). Despite similar 4-h blood glucose areas, large reductions were seen in serum insulin (54 +/- 10%, P less than 0.001) and C-peptide (47 +/- 12%, P less than 0.01) areas after sipping, together with lower gastric inhibitory polypeptide and enteroglucagon levels and urinary catecholamine output. There was also prolonged suppression of plasma glucagon, growth hormone, and free-fatty acid (FFA) levels after sipping, whereas these levels rose 3-4 h after the glucose bolus. An intravenous glucose tolerance test at 4 h demonstrated a 48 +/- 10% (P less than 0.01) more rapid decline in blood glucose (Kg) after sipping than after the bolus. Furthermore, FFA and total branched-chain amino acid levels as additional markers of insulin action were lower over this period despite similar absolute levels of insulin and C-peptide. These findings indicate that prolonging the rate of glucose absorption enhances insulin economy and glucose disposal.

Abnormalities of plasma and erythrocyte essential fatty acid composition in epidermolysis bullosa: influence of treatment with diphenylhydantoin.

The fatty acid composition of plasma and erythrocyte phospholipids was determined in children with various subtypes of epidermolysis bullosa (EB) and in their parents. Patients with recessive dystrophic, dominant dystrophic, simplex, or junctional forms of EB had a higher percentage composition of arachidonic acid in plasma and/or erythrocyte phospholipids compared to age-matched controls. Epidermolysis bullosa patients treated with diphenylhydantoin had lower levels of arachidonic acid in plasma and erythrocyte phospholipids than did untreated EB patients. Parents of children with the recessive dystrophic or junctional EB subtypes had higher linoleic and arachidonic acids in plasma and erythrocyte phospholipids than did controls. Plasma and erythrocyte total lipids were within the normal range in children with EB. Plasma zinc was also normal but plasma copper was elevated in children with recessive dystrophic EB. We conclude that higher arachidonic acid in plasma and erythrocytes may be related to the pathology of EB.

Prolactin and zinc effects on rat vascular reactivity: possible relationship to dihomo-gamma-linolenic acid and to prostaglandin synthesis.

Ovine PRL at low concentrations potentiated pressor responses to norepinephrine and angiotensin in an isolated perfused rat mesenteric vascular preparation. Higher concentrations inhibited these pressor responses. Pressor responses to potassium which depend on extracellular calcium entry into the muscle were unaffected by PRL at any concentration. Either cortisol or lithium could completely block the PRL effect. Dihomo-gamma-linolenic acid (DHGL) and prostaglandin E1 had effects similar to those of PRL in that they potentiated norepinephrine responses at low concentrations, inhibited at high ones, and had no effect on potassium responses. Arachidonic acid and prostaglandin E2 potentiated both norepinephrine and potassium responses and had no inhibitory effects at high concentrations. Neither lithium nor cortisol blocked the effects of DHGL or arachidonic acid. Zinc had actions similar to those of PRL and DHGL, but which could be blocked only by lithium and not by cortisol. These results are consistent with the concept that PRL increases synthesis of the 1 series of prostaglandins by mobilizing DHGL. They provide further evidence that zinc may play a role in some actions of PRL.

Carbon-by-carbon discrimination of 13C incorporation into liver fatty acids.

Quantitative carbon-by-carbon analysis would be useful in determining the origin and fate of carbons involved in fatty acid metabolism. Incorporation of 13C from 2-[13C]acetate into specific carbons of liver fatty acids was lowest at the n-2 carbon of saturates and monoenes but was 47% greater at acyl C1 than at C2, suggesting substantial redistribution of the 13C from C2 to C1 of acetyl CoA or malonyl CoA prior to 13C incorporation into fatty acids during de novo synthesis or during elongation. Thus, 13C derived from exogenous acetate can be quantitatively measured and is differentially incorporated into individual carbons depending on position in the fatty acid molecule.

Short-term energy deficit causes net accumulation of linoleoyl-enriched triacylglycerols in rat liver.

Energy depletion by reduced food intake over 4 days resulted in a 73% reduction in total rat liver triacylglycerols (TG). In liver TG of energy-depleted rats, dilinoleoyl oleoyl glycerol (OLL) and trilinoleoyl glycerol (LLL) were quantitatively increased by 85% and 147%, respectively. The net increase in linoleoyl-enriched species could be quantitatively accounted for by the release of linoleate from monolinoleoyl species and its subsequent reacylation into dilinoleoyl species and trilinolein during energy depletion. Hence while palmitate, oleate and some linoleate are being hydrolyzed, presumably for oxidation, some linoleate is retained and contributes to the remodelling of hepatic triacylglycerols during energy deficit.

The profile of long-chain fatty acids in serum phospholipids: a possible indicator of copper status in humans.

In previous reports of experimental copper depletion in humans, it was difficult to reliably demonstrate biochemically that there was Cu depletion. In view of the changes in serum phospholipid fatty acid profiles in Cu-deficient rats, it was considered worthwhile to determine the effect of Cu depletion in humans on serum fatty acid profiles. Serum samples from the Cu-depletion study of Reiser et al were analyzed for phospholipid fatty acid composition. After the participants had been on the low copper diet for 11 wk, serum phospholipids contained 27% less oleic acid, 38% more arachidonic acid, and 94% more docosahexaenoic acid (all p less than 0.01) than samples taken from the same subjects before Cu depletion. These fatty acid changes were of a similar direction and magnitude to those in moderately Cu-depleted rats and may be useful as an index of moderate Cu depletion in humans.

Transient neonatal zinc deficiency.

We report an infant who developed clinical manifestations of zinc deficiency during the first month of life although the diet was adequate for zinc and no other causes could be ascertained. The diagnosis was confirmed by low plasma-zinc concentrations and a positive response to zinc treatment. The fatty acid profile of plasma phospholipids was typical of zinc deficiency (ie, arachidonic acid was markedly decreased). The transient nature of this disorder was evident when no relapse occurred after cessation of zinc therapy and plasma-zinc and arachidonic acid concentrations remained normal. Several explanations for the development of transient neonatal zinc deficiency are offered. The observation demonstrates that occasional infants may have requirements for zinc that are beyond the intakes of the conventional RDA.

Beta-oxidation of linoleate in obese men undergoing weight loss.

BACKGROUND: In animals, the whole-body content and accumulation of linoleate can be measured and compared with its intake to determine linoleate beta-oxidation. This method can also provide quantitative information about the beta-oxidation of linoleate in humans. OBJECTIVES: The objectives of the study were to 1) use the wholebody fatty acid balance method to quantify whole-body concentrations of linoleate in humans, 2) estimate the distribution of linoleate between adipose and lean tissue, and 3) assess the effect of weight loss on linoleate stores and beta-oxidation in obese humans. DESIGN: Nine healthy obese men underwent supervised weight loss for 112 d (16 wk). Magnetic resonance imaging data and fatty acid profiles from fat biopsies were both used to determine linoleate stores in adipose and lean tissue and in the whole body. Linoleate beta-oxidation was calculated as intake - (accumulation + excretion). RESULTS: Mean weight loss was 13 kg and linoleate intake was 24 +/- 6 mmol/d over the study period. Whole-body loss of linoleate was 37 +/- 18 mmol/d, or 28% of the level before weight loss. Combining the intake and whole-body loss of linoleate resulted in linoleate beta-oxidation exceeding intake by 2.5-fold during the weight-loss period. CONCLUSIONS: All dietary linoleate is beta-oxidized and at least an equivalent amount of linoleate is lost from the body during moderate weight loss in obese men. The method studied permits the assessment of long-term changes in linoleate homeostasis in obese humans and may be useful in determining the risk of linoleate deficiency in other conditions.

Propionate inhibits incorporation of colonic [1,2-13C]acetate into plasma lipids in humans.

Acetate and propionate, produced during colonic fermentation of unabsorbed carbohydrate, may influence systemic lipid metabolism. As a preliminary study to see whether colonic acetate is incorporated into plasma lipids and whether propionate inhibits this process, 5 healthy males were studied after fasting overnight. They were given, in random order, 12.5 mmol (1.05 g) [1,2-13C]sodium acetate by intravenous or rectal infusion, and the rectal infusion was given with or without 6 mmol (0.58 g) sodium propionate. Two hours after rectal acetate, 13C recoveries in plasma cholesterol (0.59 +/- 0.22%) and triglycerides (1.24 +/- 0.69%) were significantly greater than after intravenous acetate (0.09 +/- 0.12% and 0.29 +/- 0.18%, respectively). Addition of propionate reduced 13C recovery in triglycerides (0.19 +/- 0.06%, P = 0.024) compared with rectal acetate alone, but the effect on cholesterol (0.26 +/- 0.05%) was not significant. These data suggest that incorporation of colonic acetate into plasma triglycerides is inhibited by propionate. Further studies are required to quantify the effects of colonic acetate and propionate on lipid synthesis.

Essential fatty acid and lipid profiles in plasma and erythrocytes in patients with multiple sclerosis.

This study was conducted to investigate the possible differences in erythrocyte lipid composition, which might account for the previously reported increase in erythrocyte membrane zinc levels in patients with multiple sclerosis (MS). Compared with healthy control subjects, plasma lipids in patients with MS contained less sphingomyelin but more phosphatidylserine and the cholesterol-phospholipid ratio was 42% higher in the plasma from MS patients (p less than 0.01). In erythrocytes from MS patients, phosphatidylinositol was lower and erythrocyte cholesterol per milligram protein was significantly lower than concentrations in healthy control subjects (p less than 0.01). Among the long-chain fatty acids, the omega-3 fatty acids were lower in plasma from MS patients and linoleic acid was lower in erythrocyte ghosts from MS patients (p less than 0.01). We conclude that altered levels of cholesterol in plasma and erythrocytes from MS patients may contribute to increased erythrocyte-membrane Zn in MS patients. It cannot be stated with certainty whether the altered fatty acid profiles in MS patients were a function of the disease or of altered fatty acid intake.