Impulsivity and genetic variants in DRD2 and ANKK1 moderate longitudinal associations between sleep problems and overweight from ages 5 to 11.

OBJECTIVE: Short sleep duration and sleep problems increase risks of overweight and weight gain. Few previous studies have examined sleep and weight repeatedly over development. This study examined the associations between yearly reports of sleep problems and weight status from ages 5 to 11. Although, previous studies have shown that inter-individual differences moderate the effect of short sleep duration on weight, it is not known whether inter-individual differences also moderate the effect of sleep problems on weight. We tested how the longitudinal associations between sleep problems and weight status were moderated by impulsivity and genetic variants in DRD2 and ANKK1. DESIGN: Seven-year longitudinal study. PARTICIPANTS: A total of 567 children from the Child Development Project for the analysis with impulsivity and 363 for the analysis with genetic variants. MEASUREMENTS AND RESULTS: Sleep problems and weight status were measured by mothers' reports yearly. Impulsivity was measured by teachers' reports yearly. Six single-nucleotide polymorphisms located in DRD2 and ANKK1 were genotyped. Data were analyzed using multilevel modeling. Higher average levels of sleep deprivation across years were associated with greater increases in overweight (P=0.0024). Sleep problems and overweight were associated at both within-person across time (P<0.0001) and between-person levels (P<0.0001). Impulsivity and two polymorphisms, rs1799978 and rs4245149 in DRD2, moderated the association between sleep problems and overweight; the association was stronger in children who were more impulsive (P=0.0022), in G allele carriers for rs1799978 (P=0.0007) and in A allele carriers for rs4245149 (P=0.0002). CONCLUSIONS: This study provided incremental evidence for the influence of sleep problems on weight. Findings of DRD2, ANKK1 and impulsivity are novel; they suggest that reward sensitivity and self-regulatory abilities might modulate the influences of sleep on weight gain. The analysis of polymorphisms was restricted to European Americans and hence the results might not generalize to other populations.

A latent class approach to the external validation of respiratory and non-respiratory panic subtypes.

BACKGROUND: The phenotypic variance observed in panic disorder (PD) appears to be best captured by a respiratory and non-respiratory panic subtype. We compared respiratory and non-respiratory panic subtypes across a series of external validators (temporal stability, psychiatric co-morbidity, treatment response) to determine whether subtypes are best conceptualized as differing: (1) only on their symptom profiles with no other differences between them; (2) on a quantitative (i.e. severity) dimension only; or (3) qualitatively from one another. METHOD: Data from a large epidemiological survey (National Epidemiologic Survey on Alcohol and Related Conditions) and a clinical trial (Cross-National Collaborative Panic Study) were used. All analytic comparisons were examined within a latent class framework. RESULTS: High temporal stability of panic subtypes was observed, particularly among females. Respiratory panic was associated with greater odds of lifetime major depression and a range of anxiety disorders as well as increased treatment utilization, but no demographic differences. Treatment outcome data did not suggest that the two PD subtypes were associated with differential response to either imipramine or alprazolam. CONCLUSIONS: These data suggest that respiratory and non-respiratory panic represent valid subtypes along the PD continuum, with the respiratory variant representing a more severe form of the disorder.

Relationship between testosterone supplementation and insulin-like growth factor-I levels and cognition in healthy older men.

BACKGROUND: Our laboratory has previously reported that testosterone (T) administration to older men significantly improves cognitive function. This study examined potential changes in insulin-like growth factor (IGF) IGF-I, IGF-II and IGF-related binding proteins in response to T administration in older men and their relationship to cognitive functioning. METHODS: Twenty-five healthy community dwelling volunteers, ranging in age from 50-80 years were randomized to receive weekly intra-muscular (i.m.) injections of either 100 mg T enanthate or placebo (saline) for 6 weeks. Serum hormone levels and cognitive functioning was assessed at baseline and twice during treatment. RESULTS: Significant positive associations between IGF-I and IGF-II and spatial memory, spatial reasoning, and verbal fluency were observed after 6 weeks of T administration. Increased serum T levels from treatment were positively associated with improvement in spatial reasoning performance, whereas estradiol was associated with a decline in divided attention performance. Serum IGF-I, IGF-II and IGFBPs did not change in response to T treatment. CONCLUSIONS: Our results suggest that T, estradiol and IGF-I may have independent and selective effects on cognitive functioning. Positive associations between T levels and cognition are consistent with an effect of androgen treatment, whereas positive associations between IGF-I levels and cognition are reflective of a relationship between endogenous IGF-I levels and cognition.

Testosterone supplementation improves spatial and verbal memory in healthy older men.

OBJECTIVE: To determine the relationship between exogenous testosterone administration and cognitive abilities in a population of healthy older men. BACKGROUND: Serum levels of total and bioavailable testosterone gradually decrease with age in men and are associated with reductions in muscle mass, osteoporosis, decreased sexual activity, and changes in cognition. METHODS: Twenty-five healthy, community-dwelling volunteers, aged 50 to 80 years, completed a randomized, double-blind, placebo-controlled study. Participants received weekly intramuscular injections of either 100 mg testosterone enanthate or placebo (saline) for 6 weeks. Cognitive evaluations were conducted at baseline, week 3, and week 6 of treatment by use of a battery of neuropsychologic tests. RESULTS: Circulating total testosterone was raised an average of 130% from baseline at week 3 and 116% at week 6 in the treatment group. Because of aromatization of testosterone, estradiol increased an average of 77% at week 3 and 73% at week 6 in the treatment group. Significant improvements in cognition were observed for spatial memory (recall of a walking route), spatial ability (block construction), and verbal memory (recall of a short story) in older men treated with testosterone compared with baseline and the placebo group, although improvements were not evident for all measures. CONCLUSIONS: The results suggest that short-term testosterone administration enhances cognitive function in healthy older men. However, it remains unclear whether these improvements in cognition are attributable to increased testosterone or estradiol levels, or both. The potential role of testosterone vs its metabolites on cognition requires further research.

Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose.

BACKGROUND: Increasing plasma glucose levels improves memory in patients with Alzheimer disease (AD). Increasing plasma glucose levels also increases endogenous insulin levels, raising the question of whether memory improvement is due to changes in insulin, independent of hyperglycemia. We address this question by examining memory and counterregulatory hormone response during hyperglycemia when endogenous insulin was suppressed by concomitant infusion of the somatostatin analogue octreotide (Sandostatin). METHODS: Twenty-three patients with AD and 14 similarly aged healthy adults participated in 4 metabolic conditions on separate days: (1) hyperinsulinemia (538 pmol/L) with fasting glucose (5.6 mmol/L [100 mg/dL]), achieved by insulin and variable dextrose infusion; (2) hyperglycemia (12.5 mmol/L [225 mg/dL]) with fasting insulin (57 pmol/L), achieved by dextrose and somatostatin (octreotide) infusion (150 mg/h); (3) placebo with isotonic sodium chloride solution (saline) infusion (fasting insulin and glucose); and (4) an active control condition in which somatostatin alone was infused (150 mg/h). Declarative memory (story recall) and selective attention (Stroop interference test) were measured during steady metabolic states. RESULTS: Patients with AD showed improved memory during hyperinsulinemia relative to placebo (P = .05) and relative to hyperglycemia (P<.005). Memory did not improve during hyperglycemia when insulin was suppressed. Somatostatin analogue infusion alone also improved memory for patients with AD (P<.05). Hyperinsulinemia increased cortisol levels in subjects with AD, whereas somatostatin alone lowered cortisol concentrations. CONCLUSIONS: These results confirm that elevated insulin without hyperglycemia enhances memory in adults with AD, and indicate that insulin is essential for hyperglycemic memory facilitation. These results also suggest a potential therapeutic role for somatostatin in AD.

Insulin metabolism in Alzheimer's disease differs according to apolipoprotein E genotype and gender.

Higher fasting plasma insulin levels and reduced CSF-to-plasma insulin ratios, suggestive of insulin resistance, have been observed in patients with Alzheimer's disease (AD) who do not possess an apolipoprotein E (APOE)-epsilon4 allele. We examined the relationship of APOE and gender to peripheral insulin action and hyperinsulinemic memory facilitation in patients with AD using a sensitive measure of insulin-mediated glucose disposal. Participants were 32 patients with AD (9 without an epsilon4 allele, 23 with an epsilon4 allele) and 25 healthy age-matched adults (16 without an epsilon4 allele, 9 with an epsilon4 allele). AD subjects without an epsilon4 allele had significantly lower insulin-mediated glucose disposal rates than AD patients with an epsilon4 allele (p < 0.03), or than normal adults without an epsilon4 allele (p < 0.02). Female AD subjects showed lower insulin-mediated glucose disposal rates than did male AD subjects (p < 0.02). No significant interaction was observed between APOE group and gender, suggesting that these effects are independent. AD subjects without an epsilon4 allele also showed significant memory facilitation in the hyperinsulinemic condition (p < 0.04), whereas the AD-epsilon4 group did not. Also in the hyperinsulinemic condition, AD patients without an epsilon4 allele had lower insulin levels than patients with an epsilon4 allele (p < 0.02), and women with AD had lower insulin levels than did men with AD despite similar insulin infusion rates and body mass (p < 0.004). No gender or genotype effects were observed in either condition for normal subjects. These results provide in vivo evidence of differences in insulin-mediated energy metabolism between epsilon4 and non-epsilon4 AD, and suggest that defective insulin action may be of particular pathophysiologic significance for patients without an epsilon-4 allele.