Adipose Tissue,Muscle, and Function: Potential Mediators of Associations Between Body Weight and Mortality in Older Adults With Type 2 Diabetes

OBJECTIVEStudies in type 2 diabetes report both increased mortality for normal weight and no evidence of an obesity paradox. We aimed to examine whether adipose tissue, muscle size, and physical function, which are known to vary by weight, mediate associations between BMI and mortality.RESULTSThe median follow-up was 6.66 years, and there were 85, 59, and 44 deaths among normal weight, overweight, and obese participants, respectively. There was no mortality risk for obese participants and an increased risk among normal weight compared with overweight participants (HR 1.72 [95% CI 1.12–2.64]). Associations remained with adjustment for adipose tissues and knee extensor strength; however, mortality risk for normal weight was attenuated following adjustment for thigh muscle (HR 1.36 [95% CI 0.87–2.11]) and gait speed (HR 1.44 [95% CI 0.91–2.27]). Linear regression confirmed with bootstrapping indicated that thigh muscle size mediated 46% of the relationship between normal weight and mortality.CONCLUSIONSNormal weight participants had elevated mortality risk compared with overweight participants. This paradoxical association was mediated in part by muscle size.     

Effect of Hypoglycemia on Brain Structure in People With Type 2 Diabetes: Epidemiological Analysis of the ACCORD-MIND MRI Trial

OBJECTIVEThe effect of hypoglycemia related to treatment of type 2 diabetes mellitus (T2DM) on brain structure remains unclear. We aimed to assess whether symptomatic severe hypoglycemia is associated with brain atrophy and/or white matter abnormalities.RESULTSOf the 503 T2DM participants (mean age, 62 years) with successful baseline and 40-month brain MRI, 28 had at least one HA episode during the 40-month follow-up. Compared with participants without HA, those with HA had marginally significant less atrophy (less decrease in TBV) from baseline to 40 months (−9.55 [95% CI −15.21, −3.90] vs. −15.38 [95% CI −16.64, −14.12], P = 0.051), and no significant increase of AWM volume (2.06 [95% CI 1.71, 2.49] vs. 1.84 [95% CI 1.76, 1.91], P = 0.247). In addition, no unexpected local signal changes or volume loss were seen on hypoglycemic participants’ brain MRI scans.CONCLUSIONSOur study suggests that hypoglycemia related to T2DM treatment may not accentuate brain pathology, specifically brain atrophy or white matter abnormalities.     

The Cross-sectional and Longitudinal Associations of Diabetic Retinopathy With Cognitive Function and Brain MRI Findings: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial

OBJECTIVELongitudinal evidence linking diabetic retinopathy with changes in brain structure and cognition is sparse. We used data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to determine whether diabetic retinopathy at baseline predicted changes in brain structure or cognition 40 months later.RESULTSBaseline retinopathy was associated with lower gray matter volume (adjusted means of 470, 466, and 461 cm³ for none, mild, and moderate/severe retinopathy, respectively; P = 0.03). Baseline retinopathy also predicted a greater change in MMSE and DSST scores at 40 months in each retinopathy category (MMSE: −0.20, −0.57, and −0.42, respectively [P = 0.04]; DSST: −1.30, −1.84, and −2.89, respectively[P = 0.01]).CONCLUSIONSDiabetic retinopathy is associated with future cognitive decline in people with type 2 diabetes. Although diabetic retinopathy is not a perfect proxy for diabetes-related brain and cognitive decline, patients with type 2 diabetes and retinopathy represent a subgroup at higher risk for future cognitive decline.     

Subclinical atherosclerotic calcification and cognitive functioning in middle-aged adults: The CARDIA study

Objective

Cardiovascular risk factors in middle-age are associated with cognitive impairment and dementia in older age. Less is known about the burden of calcified subclinical atherosclerosis and cognition, especially in midlife. We examined the association of coronary artery and abdominal aortic calcified plaque (CAC and AAC, respectively) with cognitive functioning in middle-aged adults.

Methods

This cross-sectional study included 2510 black and white adults (age: 43–55 years) without heart disease or stroke who completed a year 25 follow-up exam (2010–11) as part of the Coronary Artery Risk Development in Young Adults Study. CAC and AAC were measured with non-contrast computed tomography. Cognition was assessed with the Digit Symbol Substitution Test (DSST) (psychomotor speed), Stroop Test (executive function), and Rey Auditory Verbal Learning Test (RAVLT) (verbal memory).

Results

A greater amount of CAC and AAC was associated with worse performance on each test of cognitive function after adjustment for age, sex, race, education, and study center. Associations were attenuated, but remained significant for the DSST and RAVLT following additional adjustment for vascular risk factors, including adiposity, smoking, alcohol use, dyslipidemia, hypertension, and diabetes. Compared to participants without CAC or AAC, those with both CAC and AAC, but not CAC or AAC alone was associated with lower DSST scores (p < 0.05).

Conclusions

In this community-based sample, greater subclinical atherosclerotic calcification was associated with worse psychomotor speed and memory in midlife. These findings underscore the importance of a life course approach to the study of cognitive impairment with aging.     

Increased survival of rat EGF-generated CNS precursor cells using B27 supplemented medium

Previous studies suggest that a population of precursor cells from the developing and adult mouse striatum can be expanded in culture using serum-free, N2-supplemented medium and mitogenic factors such as epidermal growth factor (EGF). Here we show that EGF-responsive precursor cells from embryonic rat striatum and mesencephalon can also be expanded in culture, incorporate bromodeoxy uridine (BrDU) and develop into spheres that either adhere to the surface of the culture dish or float freely in the medium. Addition of B27, a medium supplement that increases neuronal survival in primary CNS cultures, resulted in a tenfold increase in the number of proliferating cells in vitro over the first week. The effects of B27-supplemented medium on precursor cell survival were only seen when primary cultures were used, such that dividing cells grown in B27 for 1 week could then be transferred to either B27 or N2 medium and show similar survival and division rates in response to EGF. After 1, 2 or 4 weeks of growth in B27-supplemented medium, dissociated precursor cells from either striatal or mesencephalic cultures could be differentiated when exposed to a poly-1-lysine-coated substrate in serum and EGF-free medium supplemented with B27. These cells then matured into a mixed culture containing neurons (approximately 35% of cells), astrocytes (approximately 44% of cells), and oligodendrocytes (approximately 10% of cells), based on immunocytochemical staining with microtuble-associated protein (MAP2), glial fibriallary acidic protein and galactocerebrosidase. When whole spheres of precursor cells were allowed to differentiate, every one examined was found to generate neurons, astrocytes and oligodendrocytes in similar proportions. Our findings suggest that B27-supplemented medium provides an enhanced environment for dividing and differentiating multi-potential precursor cells over the first week in vitro. This culture system gives an expandable source of well-characterised, multipotential CNS precursors that can be labelled with BrdU and, as such, may prove useful for either differentiation experiments in vitro or as a source of tissue for grafting into the damaged CNS.     

Co-factors affecting substance abuse among homosexual men: an investigation within a midwestern gay community

In an effort to begin formation of an empirically based model of gay substance abuse, this study examined the effects of three psychosocial factors, homosexual identity formation, self-esteem and a familial history of substance abuse in the evolution of this phenomenon among homosexual men, a group that appears to manifest appreciably higher rates and concomitantly greater associated problems than the general population. Data were obtained by voluntary subject return of a self-report instrument that was distributed widely over a 6 month period in the metropolitan Cleveland area, resulting in a moderately sized sample. Although the sampling method limited the generalizibility of the results, diminished self-esteem and a familial history of substance abuse had significant associations with both alcohol and drug abuse and were confirmed to be salient predictors, together accounting for almost half the variance in alcohol abuse and over one-third the variance in drug abuse. Moreover, both had the ability to significantly discern between alcohol and drug use groups versus groups found to be alcohol and drug abusive. Levels of a gay identity were not meaningfully associated with substance abuse. Finally, recommendations for further research were explicated.     

Survival and Differentiation of Rat and Human Epidermal Growth Factor-Responsive Precursor Cells Following Grafting into the Lesioned Adult Central Nervous System

Epidermal Growth Factor (EGF)-responsive stem cells isolated from the developing central nervous system (CNS) can be expanded exponentially in culture while retaining the ability to differentiate into neurons and glia. As such, they represent a possible source of tissue for neural transplantation, providing they can survive and mature following grafting into the adult brain. In this study we have shown that purified rat stem cells generated from either the embryonic mesencephalon or the striatum can survive grafting into the striatum of rats with either ibotenic acid or nigrostriatal dopamine lesions. However, transplanted stem cells do not survive as a large mass typical of primary embryonic CNS tissue grafts, but in contrast form thin grafts containing only a small number of surviving cells. There was no extensive migration of transplanted stem cells labeled with either thelac-zgene or bromodeoxyuridine into the host region surrounding the graft, although a small number of labeled cells were seen in the ventral striatum some distance from the site of implantation. Some of these appeared to differentiate into dopamine neurons, particularly when the developing mesencephalon was used as the starting material for generating the stem cells. EGF-responsive stem cells could also be isolated from the mesencephalon of developing human embryos and expanded in culture, but only grew in large numbers when the gestational age of the embryo was greater than 11 weeks. Purified human CNS stem cells were also transplanted into immunosuppressed rats with nigrostriatal lesions and formed thin grafts similar to those seen when using rat stem cells. However, when primary cultures of human mesencephalon were grown with EGF for only 10 days and this mixture of stem cells and primary neural tissue was transplanted into the dopamine-depleted striatum, large well-formed grafts developed. These contained mostly small undifferentiated cells intermixed with a number of well-differentiated TH-positive neurons. These results show that purified populations of rat or human EGF-responsive CNS stem cells do not form large graft masses or migrate extensively into the surrounding host tissues when transplanted into the adult striatum. However, modifications of the growth conditionsin vitromay lead to an improvement of their survivalin vivo.