Marie-Eve Paradis

Shared Neurocognitive Dysfunctions in Young Offspring at Extreme Risk for Schizophrenia or Bipolar Disorder in Eastern Quebec Multigenerational Families

BACKGROUND Adult patients having schizophrenia (SZ) or bipolar disorder (BP) may have in common neurocognitive deficits. Former evidence suggests impairments in several neuropsychological functions in young offspring at genetic risk for SZ or BP. Moreover, a dose-response relation may exist between the degree of familial loading and cognitive impairments. This study examines the cognitive functioning of high-risk (HR) offspring of parents having schizophrenia (HRSZ) and high-risk offspring of parents having bipolar disorder (HRBP) descending from densely affected kindreds. METHODS The sample consisted of 45 young offspring (mean age of 17.3 years) born to a parent having SZ or BP descending from large multigenerational families of Eastern Québec that are densely affected by SZ or BP and followed up since 1989. The offspring were administered a lifetime best-estimate diagnostic procedure (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]) and an extensive standard neuropsychological battery. Raw scores were compared with age- and gender-matched controls. RESULTS The offspring displayed differences in memory and executive functions when compared with controls. Moderate to large effect sizes (Cohen d) ranging from 0.65 to 1.25 (for IQ and memory) were observed. Several of the cognitive dysfunctions were present in both HRSZ and HRBP, even when considering DSM-IV clinical status. CONCLUSIONS HRSZ and HRBP shared several aspects of their cognitive impairment. Our data suggest that the extremely high genetic and familial loading of these HRs may have contributed to a quantitatively increased magnitude of the cognitive impairments in both HR subgroups, especially in memory. These offspring at heightened risk present difficulties in processing information that warrant preventive research.

Endothelial lipase is associated with inflammation in humans.

The aim of this study was to investigate the extent to which inflammation is linked with plasma endothelial lipase (EL) concentrations among healthy sedentary men. Plasma C-reactive protein (CRP) concentrations were measured with a highly sensitive commercial immunoassay, plasma interleukin-6 (IL-6) concentrations were measured using a commercial ELISA, and plasma secretory phospholipase A2 type IIA (sPLA2-IIA) concentrations were measured using a commercial assay in a sample of 74 moderately obese men (mean body mass index, 29.8 ± 5.2 kg/m2). Plasma EL concentrations were positively correlated with various indices of obesity, fasting plasma insulin, and plasma CRP, IL-6, and sPLA2-IIA concentrations. Multiple regression analyses revealed that plasma CRP concentrations explained 14.5% (P = 0.0008) of the variance in EL concentrations. When entered into the model, LPL activity accounted for 16.1% (P < 0.0001) and plasma CRP concentrations accounted for 20.9% (P < 0.0001) of the variance in EL concentrations. The combined impact of visceral adipose tissue (VAT) and of an inflammation score on EL concentrations was investigated. Among subjects with high or low VAT, those having a high inflammation score based on plasma CRP, IL-6, and sPLA2-IIA concentrations had increased plasma EL concentrations (P = 0.0005). In conclusion, our data reveal a strong association between proinflammatory cytokines and plasma EL concentrations among healthy people with low or high VAT levels.

Verbal and Visual Memory Impairments Among Young Offspring and Healthy Adult Relatives of Patients With Schizophrenia and Bipolar Disorder: Selective Generational Patterns Indicate Different Developmental Trajectories

Objective: Memory deficits have been shown in patients affected by schizophrenia (SZ) and bipolar (BP)/mood disorder. We recently reported that young high-risk offspring of an affected parent were impaired in both verbal episodic memory (VEM) and visual episodic memory (VisEM). Understanding better the trajectory of memory impairments from childhood to adult clinical status in risk populations is crucial for early detection and prevention. In multigenerational families densely affected by SZ or BP, our aim was to compare the memory impairments observed in young nonaffected offspring with memory functioning in nonaffected adult relatives and patients. Methods: For 20 years, we followed up numerous kindreds in the Eastern Québec population. After having characterized the Diagnostic and Statistical Manual of Mental Disorders phenotypes, we assessed cognition (N = 381) in 3 subsamples in these kindreds and in controls: 60 young offspring of a parent affected by SZ or BP, and in the adult generations, 92 nonaffected adult relatives and 40 patients affected by SZ or BP. VEM was assessed with the California Verbal Learning Test and VisEM with the Rey figures. Results: The VEM deficits observed in the offspring were also found in adult relatives and patients. In contrast, the VisEM impairments observed in the young offspring were present only in patients, not in the adult relatives. Conclusion: Implications for prevention and genetic mechanisms can be drawn from the observation that VEM and VisEM would show distinct generational trajectories and that the trajectory associated with VisEM may offer a better potential than VEM to predict future risk of developing the disease.

Visceral obesity attenuates the effect of the hepatic lipase -514C>T polymorphism on plasma HDL-cholesterol levels in French-Canadian men.

UNLABELLED The dyslipidemic state of visceral obesity is characterized by increased plasma triglyceride (TG) levels, low HDL-cholesterol concentrations and alterations in LDL composition and concentration. A functional, non-coding -514C>T single nucleotide polymorphism (SNP) of the hepatic lipase gene (LIPC) has been related to variation in HDL-cholesterol concentrations. OBJECTIVES To investigate the hypotheses that the LIPC -514C>T polymorphism may be associated with a deteriorated lipoprotein-lipid profile and that environmental factor, such as abdominal obesity, alters this association. METHODS A total of 235 French-Canadian men from the greater Quebec City area were assigned into three groups on the basis of their LIPC -514C>T SNP, including 149 CC homozygotes, 75 CT heterozygotes, and 11 TT homozygotes. RESULTS In the present study, the highest values of BMI, waist circumference, and accumulation of visceral adipose tissue (VAT) were observed among TT homozygotes (p<0.05). After adjustment for age and BMI, TT homozygotes still showed higher plasma apolipoprotein (apo) AI and HDL-TG concentrations than the two other groups (p<0.05). When the two genotype groups (CC vs CT/TT) were further divided on the basis of VAT accumulation using a cut-off point of 130 cm(2) (high vs low) it appears that irrespective of the genotype subjects with low VAT had higher HDL(2)-cholesterol concentrations (p<0.0001). However, lean carriers of the T allele had higher plasma HDL(2)-cholesterol levels than lean CC homozygotes. The beneficial effect of the T allele on plasma HDL(2)-cholesterol levels was abolished in the presence of visceral obesity (VAT>130 cm(2)). CONCLUSION In summary, the presence of visceral obesity attenuates the impact of the LIPC -514C>T polymorphism on plasma HDL(2)-cholesterol levels.

Clinical diagnoses in young offspring from eastern Québec multigenerational families densely affected by schizophrenia or bipolar disorder

Objective:  The follow‐up since 1989 of a large sample of multigenerational families of eastern Québec that are densely affected by schizophrenia (SZ) or bipolar disorder (BP) has permitted to look at the rates of DSM diagnoses in the young offspring of a SZ parent (HRSZ) and of a BP parent (HRBP) who had an extremely loaded family history.

Endothelial lipase and the metabolic syndrome

Purpose of review Several in-vitro and in-vivo animal studies indicate that endothelial lipase plays a key role in the intravascular remodeling of lipoproteins, particularly HDL. This review integrates this body of knowledge with more recent data in humans linking endothelial lipase to HDL metabolism and other features of the metabolic syndrome. Recent findings Human studies generally support the involvement of endothelial lipase in modulating plasma HDL. The association between endothelial lipase and metabolism of apolipoprotein B-containing lipoproteins in humans, however, has not been entirely consistent with previous findings in vitro and in animals. Finally, elevated plasma endothelial lipase has been associated with abdominal obesity and hypertension, and there is now compelling evidence that inflammation and in-vivo regulation of endothelial lipase may be intrinsically related. Summary Accumulating evidence indicates that endothelial lipase plays a role in the etiology of the atherogenic plasma lipoprotein profile characteristic of the metabolic syndrome. Increased endothelial lipase activity is linked to the underlying proinflammatory state in this condition. Further studies are required, however, to define the extent to which endothelial lipase contributes to the dyslipidemia of the metabolic syndrome relative to other important regulating factors, such as lipoprotein lipase, hepatic lipase, and cholesterol ester transfer protein.

A randomised crossover placebo-controlled trial investigating the effect of brown seaweed (Ascophyllum nodosum and Fucus vesiculosus) on postchallenge plasma glucose and insulin levels in men and women

This study examined the impact of brown seaweed on post-load plasma glucose and insulin concentrations in men and women. Twenty-three participants (11 men, 12 women) aged 19-59 years were recruited in this double-blind, randomized, placebo-controlled crossover study. The test product consisted of a commercially available blend of brown seaweed (Ascophyllum nodosum and Fucus vesiculosus) with known inhibitory action on α-amylase and α-glucosidase activities (InSea²). Two 250 mg seaweed capsules and 2 placebo capsules were consumed on each occasion 30 min prior to the consumption of 50 g of carbohydrates from bread. Plasma glucose and insulin concentrations were measured over a period of 3 h postcarbohydrate ingestion at predetermined time points. Both treatments were separated by a 1-week washout period. Data were analysed using mixed models for repeated measures. Compared with placebo, consumption of seaweed was associated with a 12.1% reduction in the insulin incremental area under the curve (p = 0.04, adjusted for baseline) and a 7.9% increase in the Cederholm index of insulin sensitivity (p < 0.05). The single ingestion of 500 mg of brown seaweed had no significant effect on the glucose response (p = 0.24, adjusted for baseline). Glucose and insulin responses were similar between men and women. Consumption of the seaweed capsules was not associated with any adverse event. These data suggest that brown seaweed may alter the insulin homeostasis in response to carbohydrate ingestion.

Apolipoprotein A-I, A-II, and VLDL-B-100 metabolism in men: comparison of a low-fat diet and a high-monounsaturated fatty acid diet

The impact of a low-fat diet and a high-MUFA diet on apolipoprotein A-I (apoA-I), apoA-II, and VLDL-apoB-100 metabolism in conditions of unrestricted (ad libitum) energy intake was compared in 65 men randomly assigned to one of two predefined experimental diets. A subsample of 18 men participated in the kinetic study. Before and after the 6–7 week dietary intervention, kinetic subjects received a primed-constant infusion of [5,5,5-2H3]l-leucine for 12 h under feeding conditions. ApoA-I production rate (PR; −31.5%; P < 0.001) and fractional catabolic rate (FCR; −24.3%; P < 0.05) were significantly decreased after the low-fat diet. These changes in apoA-I PR and FCR with the low-fat diet were also significantly different from those observed with the high-MUFA diet (P < 0.01 and P < 0.05, respectively). ApoA-II FCR was significantly increased in the high-MUFA group only. No significant within- or between-diet difference was found in VLDL-apoB-100 PR or FCR. These results emphasize the differential impact of the low-fat diet and high-MUFA diet on HDL metabolism.

Intravascular Kinetics of C-Reactive Protein and Their Relationships with Features of the Metabolic Syndrome

OBJECTIVE The objective of the study was to describe, for the first time, the intravascular kinetics of C-reactive protein (CRP), using stable isotopes, and its relationship with features of the metabolic syndrome. METHODS Sixteen men and 16 women [aged 49 +/- 9 years, body mass index (BMI) 28.7 +/- 4.5 kg/m(2)] underwent a 12-h primed-constant infusion of 5,5,5-(2)H(3)-l-leucine. CRP was purified from the plasma fraction rho greater than 1.25 g/ml by affinity chromatography, and isotopic enrichment over time was determined by gas chromatography/mass spectrometry. RESULTS The CRP fractional catabolic rate was 60% higher in men than women (0.49 +/- 1.83 vs. 0.30 +/- 1.80 pool/d, P = 0.03), but this difference was no longer significant in a multivariate model that included several features associated with the metabolic syndrome. The CRP production rate (PR) and pool size were not statistically different between sexes. Plasma CRP concentrations were more strongly correlated with the PR (r = 0.80, P < 0.0001) than with the fractional catabolic rate of CRP (r = 0.39, P < 0.05). The PR of CRP was positively correlated with waist girth (r = 0.53, P < 0.01), plasma low-density lipoprotein apolipoprotein B-100 (r = 0.42, P = 0.07), triglyceride (r = 0.41, P = 0.06), and IL-6 concentrations (r = 0.61, P = 0.0008) and inversely correlated with high-density lipoprotein-cholesterol (r = -0.47, P = 0.03) and adiponectin (r = -0.63, P < 0.0005) after adjustment for sex. Blood pressure and low-density lipoprotein-cholesterol showed no association with CRP kinetics. CONCLUSION The PR of CRP appeared as the main determinant of CRP concentrations and showed significant associations with features of the metabolic syndrome as well as with adipose tissue-derived cytokines such as IL-6 and adiponectin.

Visceral adipose tissue accumulation, secretory phospholipase A2-IIA and atherogenecity of LDL.

Objective:The aim of the present study was to investigate the combined impact of visceral adipose tissue (VAT) and secretory group IIA phospholipase A2 (sPLA2-IIA) concentrations on the atherogenicity of low-density lipoprotein (LDL) particles among men.Subjects:Analyses were conducted in 74 mid-obese healthy men (age: (mean±s.d.) 37.9±11.7 years).Methods:Plasma levels of sPLA2-IIA were measured with a commercial ELISA and VAT levels were assessed by computed tomography. Distinct subpopulations of LDL particles were characterized from whole plasma using nondenaturating 2–16% gradient gel electrophoresis.Results:Data indicated that plasma sPLA2-IIA levels were approximately 29% (P=0.007) higher among men characterized by a higher accumulation of VAT (>142 vs ⩽142 cm2). Men having high plasma sPLA2-IIA levels (⩾127.2 ng/dl, the median value), were characterized by higher levels of plasma cholesterol (C) and apolipoprotein (apo) B, LDL-C, LDL-apoB, oxidized LDL (OxLDL) and by smaller LDL particles compared to men with sPLA2-IIA<127.2 ng/dl. Multiple regression analyses showed that plasma triglycerides and sPLA2-IIA levels explained 22.7 and 11.8% of the variance in LDL peak particle size, respectively. Levels of VAT and of sPLA2-IIA were the strongest correlates of OxLDL levels explaining, respectively, 15.0 and 5.5% of their variability.Conclusion:Both VAT and sPLA2-IIA levels modulate the atherogenecity of LDL by accounting for the reduction in their size and their susceptibility to oxidation.