Insulin, cognition, and dementia Cholerton, Brenna; Baker, Laura D.; Craft, Suzanne
European journal of pharmacology,
11/2013, Volume:
719, Issue:
1-3
Journal Article
Peer reviewed
Open access
Cognitive disorders of aging represent a serious threat to the social and economic welfare of current society. It is now widely recognized that pathology related to such conditions, particularly ...Alzheimer's disease, likely begins years or decades prior to the onset of clinical dementia symptoms. This revelation has led researchers to consider candidate mechanisms precipitating the cascade of neuropathological events that eventually lead to clinical Alzheimer's disease. Insulin, a hormone with potent effects in the brain, has recently received a great deal of attention for its potential beneficial and protective role in cognitive function. Insulin resistance, which refers to the reduced sensitivity of target tissues to the favorable effects of insulin, is related to multiple chronic conditions known to impact cognition and increase dementia risk. With insulin resistance-associated conditions reaching epidemic proportions, the prevalence of Alzheimer's disease and other cognitive disorders will continue to rise exponentially. Fortunately, these chronic insulin-related conditions are amenable to pharmacological intervention. As a result, novel therapeutic strategies that focus on increasing insulin sensitivity in the brain may be an important target for protecting or treating cognitive decline. The following review will highlight our current understanding of the role of insulin in brain, potential mechanisms underlying the link between insulin resistance and dementia, and current experimental therapeutic strategies aimed at improving cognitive function via modifying the brain's insulin sensitivity.
Nitric oxide (.NO)-derived reactive species nitrate unsaturated fatty acids, yielding nitroalkene derivatives, including the clinically abundant nitrated oleic and linoleic acids. The olefinic nitro ...group renders these derivatives electrophilic at the carbon β to the nitro group, thus competent for Michael addition reactions with cysteine and histidine. By using chromatographic and mass spectrometric approaches, we characterized this reactivity by using in vitro reaction systems, and we demonstrated that nitroalkene-protein and GSH adducts are present in vivo under basal conditions in healthy human red cells. Nitro-linoleic acid (9-, 10-, 12-, and 13-nitro-9,12-octadecadienoic acids) (m/z 324.2) and nitro-oleic acid (9- and 10-nitro-9-octadecaenoic acids) (m/z 326.2) reacted with GSH (m/z 306.1), yielding adducts with m/z of 631.3 and 633.3, respectively. At physiological concentrations, nitroalkenes inhibited glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which contains a critical catalytic Cys (Cys-149). GAPDH inhibition displayed an IC50 of ∼3 μmm for both nitroalkenes, an IC50 equivalent to the potent thiol oxidant peroxynitrite (ONOO−) and an IC50 30-fold less than H2O2, indicating that nitroalkenes are potent thiol-reactive species. Liquid chromatography-mass spectrometry analysis revealed covalent adducts between fatty acid nitroalkene derivatives and GAPDH, including at the catalytic Cys-149. Liquid chromatography-mass spectrometry-based proteomic analysis of human red cells confirmed that nitroalkenes readily undergo covalent, thiol-reversible post-translational modification of nucleophilic amino acids in GSH and GAPDH in vivo. The adduction of GAPDH and GSH by nitroalkenes significantly increased the hydrophobicity of these molecules, both inducing translocation to membranes and suggesting why these abundant derivatives had not been detected previously via traditional high pressure liquid chromatography analysis. The occurrence of these electrophilic nitroalkylation reactions in vivo indicates that this reversible post-translational protein modification represents a new pathway for redox regulation of enzyme function, cell signaling, and protein trafficking.
A meta-analysis of twin, family and adoption studies was conducted to estimate the magnitude of genetic and environmental influences on impulsivity. The best fitting model for 41 key studies (58 ...independent samples from 14
month old infants to adults; N
=
27,147) included equal proportions of variance due to genetic (0.50) and non-shared environmental (0.50) influences, with genetic effects being both additive (0.38) and non-additive (0.12). Shared environmental effects were unimportant in explaining individual differences in impulsivity. Age, sex, and study design (twin vs. adoption) were all significant moderators of the magnitude of genetic and environmental influences on impulsivity. The relative contribution of genetic effects (broad sense heritability) and unique environmental effects were also found to be important throughout development from childhood to adulthood. Total genetic effects were found to be important for all ages, but appeared to be strongest in children. Analyses also demonstrated that genetic effects appeared to be stronger in males than in females. Method of assessment (laboratory tasks vs. questionnaires), however, was not a significant moderator of the genetic and environmental influences on impulsivity. These results provide a structured synthesis of existing behavior genetic studies on impulsivity by providing a clearer understanding of the relative genetic and environmental contributions in impulsive traits through various stages of development.
► Meta-analyses on 41 key studies examining the heritability of impulsivity. ► Genetic and unique environmental effects were found to be equally important. ► Total genetic effects appeared to be strongest in children. ► Total genetic effects appeared to be stronger in males than in females.
The recognition of Alzheimer's disease (AD) as a heterogeneous disorder that results from incremental pathological changes in dynamic organismic systems is essential to move beyond the unidimensional ...approaches to prevention and therapy that have proven largely ineffective to date. Biological systems related to insulin metabolism are arguably the most critical regulators of longevity and corporeal aging. Our work has focused on identifying the relationship of the insulin network to brain aging, and determining the mechanisms through which insulin dysregulation promotes AD pathological processes. Candidate mechanisms include the effects of insulin on amyloid-β, cerebral glucose metabolism, vascular function, lipid metabolism, and inflammation/oxidative stress. It is likely that different nodes of the insulin network are perturbed for subgroups of AD patients, or that for some subgroups, pathways independent of insulin are critical pathogenetic factors. New methods from systems network analyses may help to identify these subgroups, which will be critical for devising tailored prevention and treatment strategies. In the following review, we will provide a brief description of the role of insulin in normal brain function, and then focus more closely on recent evidence regarding the mechanisms through which disruption of that role may promote AD pathological processes. Finally, we will discuss the implications of this area for AD therapeutics and prevention.
The Black Men’s Health Forum, a 6-week online health education intervention for African American men and accountability partners of African American men, was conducted to increase awareness of health ...issues that disproportionately affect African American men. In this article, we describe the intervention and report on the immediate benefits of the intervention, including changes in health knowledge and perception of research participation. Participants completed a pre-evaluation prior to participating in the forum and a post-evaluation after each session to capture data on sociodemographic information, medical history, health knowledge, and health behaviors. A total of 60 participants (30 African American men and 30 accountability partners) completed the forum. African American men had a mean age of 61.1 years while accountability partners had a mean age of 57.6 years. Overall health knowledge increased by 6.9 points for African American men and 2.8 points for accountability partners. Before the forum began, nine African American men reported ever participating in a research study. The proportion of African American men who reported that they would definitely participate in research in the next 12 months after participating in the forum increased by 40%. Through culturally tailored programming, the Black Men’s Health Forum increased access to health information as well as African American male medical professionals and health researchers for African American men in the community. Exposure to health information resulted in significant increases in health knowledge and willingness to participate in health research among African American men.
Previous trials have shown promising effects of intranasally administered insulin for adults with Alzheimer's disease dementia (AD) or amnestic mild cognitive impairment (MCI). These trials used ...regular insulin, which has a shorter half-life compared to long-lasting insulin analogues such as insulin detemir. The current trial examined whether intranasal insulin detemir improves cognition or daily functioning for adults with MCI or AD. Sixty adults diagnosed with MCI or mild to moderate AD received placebo (n = 20), 20 IU of insulin detemir (n = 21), or 40 IU of insulin detemir (n = 19) for 21 days, administered with a nasal drug delivery device. Results revealed a treatment effect for the memory composite for the 40 IU group compared with placebo (p < 0.05). This effect was moderated by APOE status (p < 0.05), reflecting improvement for APOE-ε4 carriers (p < 0.02), and worsening for non-carriers (p < 0.02). Higher insulin resistance at baseline predicted greater improvement with the 40 IU dose (r = 0.54, p < 0.02). Significant treatment effects were also apparent for verbal working memory (p < 0.03) and visuospatial working memory (p < 0.04), reflecting improvement for subjects who received the high dose of intranasal insulin detemir. No significant differences were found for daily functioning or executive functioning. In conclusion, daily treatment with 40 IU insulin detemir modulated cognition for adults with AD or MCI, with APOE-related differences in treatment response for the primary memory composite. Future research is needed to examine the mechanistic basis of APOE-related treatment differences, and to further assess the efficacy and safety of intranasal insulin detemir.
Long acting insulin detemir administered intranasally for three weeks enhanced memory for adults with Alzheimer's disease dementia (AD) or amnestic mild cognitive impairment (MCI). The investigation ...of longer-term administration is necessary to determine whether benefits persist, whether they are similar to benefits provided by regular insulin, and whether either form of insulin therapy affects AD biomarkers.
The present study aimed to determine whether four months of treatment with intranasal insulin detemir or regular insulin improves cognition, daily functioning, and AD biomarkers for adults with MCI or AD.
This randomized, double-blind, placebo-controlled trial included an intent-to-treat sample consisting of 36 adults diagnosed with MCI or mild to moderate AD. Participants received placebo (n = 12), 40 IU of insulin detemir (n = 12), or 40 IU of regular insulin (n = 12) daily for four months, administered with a nasal delivery device. A cognitive battery was administered at baseline and after two and four months of treatment. MRI was administered for all participants and lumbar puncture for a subset (n = 20) at baseline and four months. The primary outcome was change from baseline to four months on a memory composite (sum of Z scores for delayed list and story recall). Secondary outcomes included: global cognition (Alzheimer's Disease Assessment Scale-Cognition), daily functioning (Dementia Severity Rating Scale), MRI volume changes in AD-related regions of interest, and cerebrospinal fluid AD markers.
The regular insulin treated group had better memory after two and four months compared with placebo (p < 0.03). No significant effects were observed for the detemir-assigned group compared with the placebo group, or for daily functioning for either group. Regular insulin treatment was associated with preserved volume on MRI. Regular insulin treatment was also associated with reduction in the tau-P181/Aβ42 ratio.
Future research is warranted to examine the mechanistic basis of treatment differences, and to further assess the efficacy and safety of intranasal insulin.
Neighborhood greenspace improves mental health of urban-dwelling populations, but its putative neurobehavioral benefits in adolescents remain unclear. We conducted a prospective study on ...urban-dwelling adolescents to examine the association between greenspace in residential neighborhood and aggressive behaviors.
Participants (n = 1,287) of the Risk Factors for Antisocial Behavior Study, a multi-ethnic cohort of twins and triplets born in 1990 to 1995 and living in Southern California, were examined in 2000 to 2012 (aged 9-18 years) with repeated assessments of their aggressive behaviors by the parent-reported Child Behavior Checklist. Normalized Difference Vegetation Index (NDVI) derived from satellite imagery was used as a proxy for residential neighborhood greenspace aggregated over various spatiotemporal scales before each assessment. Multilevel mixed-effects models were used to estimate the effects of greenspace on aggressive behaviors, adjusting for within-family/within-individual correlations and other potential confounders.
Both short-term (1- to 6-month) and long-term (1- to 3-year) exposures to greenspace within 1,000 meters surrounding residences were associated with reduced aggressive behaviors. The benefit of increasing vegetation over the range (∼0.12 in NDVI) commonly seen in urban environments was equivalent to approximately 2 to 2.5 years of behavioral maturation. Sociodemographic factors (e.g., age, gender, race/ethnicity, and socioeconomic status) and neighborhood quality did not confound or modify these associations, and the benefits remained after accounting for temperature.
Our novel findings support the benefits of neighborhood greenspace in reducing aggressive behaviors of urban-dwelling adolescents. Community-based interventions are needed to determine the efficacy of greenspace as a preemptive strategy to reduce aggressive behaviors in urban environments.
Impact of adolescent marijuana use on intelligence Jackson, Nicholas J.; Isen, Joshua D.; Khoddam, Rubin ...
Proceedings of the National Academy of Sciences - PNAS,
02/2016, Volume:
113, Issue:
5
Journal Article
Peer reviewed
Open access
Marijuana is one of the most commonly used drugs in the United States, and use during adolescence—when the brain is still developing—has been proposed as a cause of poorer neurocognitive outcome. ...Nonetheless, research on this topic is scarce and often shows conflicting results, with some studies showing detrimental effects of marijuana use on cognitive functioning and others showing no significant long-term effects. The purpose of the present study was to examine the associations of marijuana use with changes in intellectual performance in two longitudinal studies of adolescent twins (n = 789 and n = 2,277). We used a quasiexperimental approach to adjust for participants’ family background characteristics and genetic propensities, helping us to assess the causal nature of any potential associations. Standardized measures of intelligence were administered at ages 9–12 y, before marijuana involvement, and again at ages 17–20 y. Marijuana use was self-reported at the time of each cognitive assessment as well as during the intervening period. Marijuana users had lower test scores relative to nonusers and showed a significant decline in crystallized intelligence between preadolescence and late adolescence. However, there was no evidence of a dose–response relationship between frequency of use and intelligence quotient (IQ) change. Furthermore, marijuana-using twins failed to show significantly greater IQ decline relative to their abstinent siblings. Evidence from these two samples suggests that observed declines in measured IQ may not be a direct result of marijuana exposure but rather attributable to familial factors that underlie both marijuana initiation and low intellectual attainment
Fatty acid nitration by nitric oxide-derived species yields electrophilic products that adduct protein thiols, inducing changes in protein function and distribution. Nitro-fatty acid adducts of ...protein and reduced glutathione (GSH) are detected in healthy human blood. Kinetic and mass spectrometric analyses reveal that nitroalkene derivatives of oleic acid (OA-NO₂) and linoleic acid (LNO₂) rapidly react with GSH and Cys via Michael addition reaction. Rates of OA-NO₂ and LNO₂ reaction with GSH, determined via stopped flow spectrophotometry, displayed second-order rate constants of 183 M⁻¹s⁻¹ and 355 M⁻¹s⁻¹, respectively, at pH 7.4 and 37 °C. These reaction rates are significantly greater than those for GSH reaction with hydrogen peroxide and non-nitrated electrophilic fatty acids including 8-iso-prostaglandin A₂ and 15-deoxy-Δ¹²,¹⁴-prostaglandin J₂. Increasing reaction pH from 7.4 to 8.9 enhanced apparent second-order rate constants for the thiol reaction with OA-NO₂ and LNO₂, showing dependence on the thiolate anion of GSH for reactivity. Rates of nitroalkene reaction with thiols decreased as the pKa of target thiols increased. Increasing concentrations of the detergent octyl-β-D-glucopyranoside decreased rates of nitroalkene reaction with GSH, indicating that the organization of nitro-fatty acids into micellar or membrane structures can limit Michael reactivity with more polar nucleophilic targets. In aggregate, these results reveal that the reversible adduction of thiols by nitro-fatty acids is a mechanism for reversible post-translational regulation of protein function by nitro-fatty acids.
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