Effect of apolipoprotein E genotype and diet on apolipoprotein E lipidation and amyloid peptides: randomized clinical trial.

IMPORTANCE: Sporadic Alzheimer disease (AD) is caused in part by decreased clearance of the ß-amyloid (Aß) peptide breakdown products. Lipid-depleted (LD) apolipoproteins are less effective at binding and clearing Aß, and LD Aß peptides are more toxic to neurons. However, not much is known about the lipid states of these proteins in human cerebrospinal fluid. OBJECTIVE: To characterize the lipidation states of Aß peptides and apolipoprotein E in the cerebrospinal fluid in adults with respect to cognitive diagnosis and APOE ε4 allele carrier status and after a dietary intervention. DESIGN: Randomized clinical trial. SETTING: Veterans Affairs Medical Center clinical research unit. PARTICIPANTS: Twenty older adults with normal cognition (mean [SD] age, 69 [7] years) and 27 with amnestic mild cognitive impairment (67 [6] years). INTERVENTIONS: Randomization to a diet high in saturated fat content and with a high glycemic index (High diet; 45% of energy from fat [>25% saturated fat], 35%-40% from carbohydrates with a mean glycemic index >70, and 15%-20% from protein) or a diet low in saturated fat content and with a low glycemic index (Low diet; 25% of energy from fat [<7% saturated fat], 55%-60% from carbohydrates with a mean glycemic index <55, and 15%-20% from protein). MAIN OUTCOMES AND MEASURES: Lipid-depleted Aß42 and Aß40 and apolipoprotein E in cerebrospinal fluid. RESULTS: Baseline levels of LD Aß were greater for adults with mild cognitive impairment compared with adults with normal cognition (LD Aß42, P = .05; LD Aß40, P = .01). These findings were magnified in adults with mild cognitive impairment and the ε4 allele, who had higher LD apolipoprotein E levels irrespective of cognitive diagnosis (P < .001). The Low diet tended to decrease LD Aß levels, whereas the High diet increased these fractions (LD Aß42, P = .01; LD Aß40, P = .15). Changes in LD Aß levels with the Low diet negatively correlated with changes in cerebrospinal fluid levels of insulin (LD Aß42 and insulin, r = -0.68 [P = .01]; LD Aß40 and insulin, r = -0.78 [P = .002]). CONCLUSIONS AND RELEVANCE: The lipidation states of apolipoproteins and Aß peptides in the brain differ depending on APOE genotype and cognitive diagnosis. Concentrations can be modulated by diet. These findings may provide insight into the mechanisms through which apolipoprotein E4 and unhealthy diets impart risk for developing AD.

How do sock ply changes affect residual-limb fluid volume in people with transtibial amputation?

The purpose of this research was to investigate the influence of sock addition and removal on residual-limb fluid volume in people using prosthetic limbs. We used bioimpedance analysis to measure residual-limb extracellular fluid volume on 28 transtibial amputee subjects during 30 min test sessions. Upon addition of a one-ply polyester sock, residual-limb fluid volume changes ranged from -4.0% to 0.8% (mean -0.9 +/- 1.3%) of the initial limb fluid volume. Changes for sock removal ranged from -1.2% to 2.8% (mean 0.5 +/- 0.8%). Subjects who reduced in fluid volume with both addition and removal of a sock and subjects with high positive ratios between the fluid-volume loss upon sock addition and gain upon sock removal (high add/remove [AR] ratios) tended to have arterial disease, were obese, and were smokers. Subjects with low positive AR ratios, subjects who increased in fluid volume both with sock addition and removal, and a single subject who increased in fluid volume with sock addition and decreased with sock removal tended to be nonsmokers and either individuals in good health without complications or individuals without arterial problems. Results are relevant for the anticipation of limb volume changes during prosthetic fitting and toward the design of adjustable-socket technologies.

High-intensity physical activity modulates diet effects on cerebrospinal amyloid-ß levels in normal aging and mild cognitive impairment.

We previously showed that amyloid-ß 1-42 (Aß(42)) levels in cerebrospinal fluid (CSF) were markedly altered in response to a 4-week dietary intervention in normal aging and mild cognitive impairment (MCI). Here, we re-examined the data to assess whether diet-induced effects on CSF Aß(42) were modulated by high intensity physical activity (hi-PA). Normal older adults (n = 18, mean age = 68.6 ± 7.4 y) and adults with amnestic MCI (n = 23, mean age = 68.0 ± 6.5 y) received a low saturated fat/low glycemic index (LOW) diet or a high saturated fat/high glycemic index (HIGH) diet, and CSF levels of Aß(42), tau, and IL-8 were measured at baseline and week 4. Pre-study activity levels were assessed using a 7-d questionnaire, and weekly duration of hi-PA was quantified. At baseline, increased hi-PA in normals predicted lower CSF levels of tau (r = -0.54, p = 0.020) and IL-8 (r = -0.70, p = 0.025). Diet-induced effects on CSF Aß(42) during the intervention study were modulated by hi-PA, and the nature of this effect differed for normals and MCI (ANOVA, p = 0.039). That is, for normal adults, increased hi-PA attenuated the effects of the HIGH diet on CSF Aß(42) whereas in MCI, increased hi-PA potentiated the effects of the LOW diet. Our results suggest that normal adults who engage in hi-PA are less vulnerable to the pathological effects of an unhealthy diet, while in MCI, the benefit of a healthy diet on Aß modulation is greatest when paired with hi-PA. Exercise may thus interact with diet to alter pathological processes that ultimately modify risk of Alzheimer's disease.

Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial.

OBJECTIVE: To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Clinical research unit of a Veterans Affairs medical center. PARTICIPANTS: The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40). Intervention  Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington). MAIN OUTCOME MEASURES: Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-cog) score and the Alzheimer's Disease Cooperative Study-activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment. RESULTS: Outcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayed memory (P < .05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P < .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P < .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aß42 level and in the tau protein-to-Aß42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions and insulin-minimized progression. No treatment-related severe adverse events occurred. CONCLUSIONS: These results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD. Trial Registration  clinicaltrials.gov Identifier: NCT00438568.

Preliminary investigation of residual-limb fluid volume changes within one day.

The purpose of this research was to investigate rates of residual-limb fluid volume change within one day for people with transtibial limb loss. Rates of fluid volume change during 30 min test sessions of sitting, standing, and walking activities were measured twice a day, once in the morning and once in the afternoon, on 12 regular prosthesis users with the use of bioimpedance analysis. Between test sessions, all subjects consumed food and drink, and subject activity ranged from low to high. The rate of fluid volume change within sessions ranged from -8.5 to 5.9 %/h (median: -2.2%/h). The rate of fluid volume change between sessions ranged from -2.7 to 0.9 %/h (median: -1.0%/h). The between-session rate of fluid volume change correlated highly with afternoon within-session rates of change (r = 0.9) but was not well correlated with morning within-session rates of change (r = 0.8). Subjects with peripheral arterial complications showed greater fluid volume loss rates during test sessions than between sessions. Rate of fluid volume change may be affected by sitting, standing, and walking activities; presence of peripheral arterial complications; being female; time since amputation; and wearing the socket without doffing for extended periods.

Diet intervention and cerebrospinal fluid biomarkers in amnestic mild cognitive impairment.

OBJECTIVE: To compare the effects of a 4-week high-saturated fat/high-glycemic index (HIGH) diet with a low-saturated fat/low-glycemic index (LOW) diet on insulin and lipid metabolism, cerebrospinal fluid (CSF) markers of Alzheimer disease, and cognition for healthy adults and adults with amnestic mild cognitive impairment (aMCI). DESIGN: Randomized controlled trial. SETTING: Veterans Affairs Medical Center clinical research unit. PARTICIPANTS: Forty-nine older adults (20 healthy adults with a mean [SD] age of 69.3 [7.4] years and 29 adults with aMCI with a mean [SD] age of 67.6 [6.8] years). INTERVENTION: Participants received the HIGH diet (fat, 45% [saturated fat, > 25%]; carbohydrates, 35%-40% [glycemic index, > 70]; and protein, 15%-20%) or the LOW diet (fat, 25%; [saturated fat, < 7%]; carbohydrates, 55%-60% [glycemic index, < 55]; and protein, 15%-20%) for 4 weeks. Cognitive tests, an oral glucose tolerance test, and lumbar puncture were conducted at baseline and during the fourth week of the diet. MAIN OUTCOME MEASURES: The CSF concentrations of ß-amyloid (Aß42 and Aß40), tau protein, insulin, F2-isoprostanes, and apolipoprotein E, plasma lipids and insulin, and measures of cognition. RESULTS: For the aMCI group, the LOW diet increased CSF Aß42 concentrations, contrary to the pathologic pattern of lowered CSF Aß42 typically observed in Alzheimer disease. The LOW diet had the opposite effect for healthy adults, ie, decreasing CSF Aß42, whereas the HIGH diet increased CSF Aß42. The CSF apolipoprotein E concentration was increased by the LOW diet and decreased by the HIGH diet for both groups. For the aMCI group, the CSF insulin concentration increased with the LOW diet, but the HIGH diet lowered the CSF insulin concentration for healthy adults. The HIGH diet increased and the LOW diet decreased plasma lipids, insulin, and CSF F2-isoprostane concentrations. Delayed visual memory improved for both groups after completion of 4 weeks of the LOW diet. CONCLUSION: Our results suggest that diet may be a powerful environmental factor that modulates Alzheimer disease risk through its effects on central nervous system concentrations of Aß42, lipoproteins, oxidative stress, and insulin.

The association between birth weight and visceral fat in middle-age adults.

OBJECTIVE: Low birth weight, a proxy for fetal underdevelopment, is associated with increased risk of developing type 2 diabetes during adulthood. Low birth weight is also associated with central obesity, but little is known about the association between birth weight and visceral adiposity. The purpose of this study is to test the hypothesis that lower birth weight is associated with increased amounts of visceral fat in middle-age adults. RESEARCH METHODS AND PROCEDURES: This is an observational study of 91 adults (58 men and 33 women) 40+/-6 years of age (mean+/-standard deviation). Ethnicity was either Japanese American (79%) or non-Hispanic white (21%). Birth weight was obtained from State Departments of Health. Measurements included smoking status, BMI, and visceral (intra-abdominal) fat measured by computed tomography. RESULTS: Visceral fat was not associated with birth weight after adjustment for age, sex, ethnicity, BMI, or smoking status (p=0.76). There was no evidence that the association between birth weight and visceral fat varied by age, sex, or ethnicity. DISCUSSION: We found no evidence that low birth weight is associated with increased visceral fat in middle-age adults.

Equivalent insulin resistance in latent autoimmune diabetes in adults (LADA) and type 2 diabetic patients.

Insulin resistance is a primary component in the pathophysiology of type 2 diabetes. In latent autoimmune diabetes in adults (LADA), insulin resistance has been reported to be significantly lower than in autoantibody-negative type 2 diabetes (T2DM), but whether this might be related to differences in body mass index (BMI) has not been excluded. Furthermore, previous studies have used limiting inclusive criteria for LADA, requiring only the presence of GADA or IA-2A. To apply more inclusive criteria for LADA, consistent with recent recommendations, we defined LADA by clinical manifestations characteristic of T2DM, but with the presence of any combination of GADA, IA-2A, ICA, or IAA. We recruited 43 LADA patients, 70 T2DM patients, and 150 non-diabetic controls. Insulin resistance was assessed by both the homeostasis model assessment and the quantitative insulin sensitivity check index, and BMI was calculated. We found that insulin resistance in LADA is equivalent to that of T2DM. When insulin resistance is assessed as a function of BMI, both diabetic populations demonstrated an insulin resistance equally greater than normal controls. The interaction between insulin resistance and BMI in the two diabetic groups was significantly different from that demonstrated in non-diabetic controls. In summary, LADA demonstrates insulin resistance of similar magnitude to T2DM, but with the concurrent component of an immune attack against the pancreatic beta-cells. LADA patients may be at significant risk for metabolic consequences of insulin resistance other than glucose metabolism, such as those described in the metabolic syndrome. As complications and treatment regimens specific to LADA are realized, improved means of identification of LADA will become increasingly important.

Is central obesity associated with cirrhosis-related death or hospitalization? A population-based, cohort study.

BACKGROUND & AIMS: We aimed to determine the interaction between body fat distribution (central versus peripheral) and increased body mass index (BMI) with regards to the risk of cirrhosis-related death or hospitalization. METHODS: Participants included 11,434 persons aged 25-74 years without evidence of cirrhosis at entry into the study or during the first 5 years of follow-up who were subsequently followed for a mean of 12.9 years as part of the first National Health and Nutrition Examination Survey. Participants were categorized into "normal-weight" (BMI < 25 kg/m 2 , N = 5750), "overweight" (BMI 25 to < 30 kg/m 2 , N = 3770), and "obese" (BMI > or = 30 kg/m 2 , N = 1914). The subscapular to triceps skinfold thickness ratio (SFR) was used to categorize body fat distribution into central (SFR > 1, N = 5211) and peripheral (SFR < or = 1, N = 6223). RESULTS: Cirrhosis resulted in death or hospitalization of 88 participants during 149,888 person-years of follow-up (59/100,000 person-years). Among persons with a central body fat distribution, cirrhosis-related deaths or hospitalizations were more common in obese persons (115/100,000 person-years, adjusted hazard ratio 2.2, 95% confidence interval [CI] 1.1-4.6) and in overweight persons (94/100,000 person-years, adjusted hazard ratio 1.5, 95% CI 0.8-3.0) compared to normal-weight persons (59/100,000 person-years). However, among persons with a peripheral fat distribution, there was no association between obesity (adjusted hazard ratio 0.7, 95% CI 0.3-1.6) or overweight (adjusted hazard ratio 0.8, 95% CI 0.2-2.8) and cirrhosis-related death or hospitalization. CONCLUSIONS: The risk of cirrhosis-related death or hospitalization appears to be increased in the presence of cirrhosis, but only among persons with a central fat distribution. The excess risk associated with central obesity might be related to insulin resistance and hepatic steatosis.

Potential of essential fatty acid deficiency with extremely low fat diet in lipoprotein lipase deficiency during pregnancy: A case report.

BACKGROUND: Pregnancy in patients with lipoprotein lipase deficiency is associated with high risk of maternal pancreatitis and fetal death. A very low fat diet (< 10% of calories) is the primary treatment modality for the prevention of acute pancreatitis, a rare but potentially serious complication of severe hypertriglyceridemia. Since pregnancy can exacerbate hypertriglyceridemia in the genetic absence of lipoprotein lipase, a further reduction of dietary fat intake to < 1-2% of total caloric intake may be required during the pregnancy, along with the administration of a fibrate. It is uncertain if essential fatty acid deficiency will develop in the mother and fetus with this extremely low fat diet, or whether fibrates will cross the placenta and concentrate in the fetus. CASE PRESENTATION: A 23 year-old gravida 1 woman with primary lipoprotein lipase deficiency was seen at 7 weeks of gestation in the Lipid Clinic for management of severe hypertriglyceridemia that had worsened with pregnancy. While on her habitual fat intake of 10% of total calories, her pregnancy resulted in an exacerbation of the hypertriglyceridemia, which prompted further restriction of fat intake to < 2% of total calories, as well as administration of gemfibrozil at a lower than average dose. The level of gemfibrozil, as the active metabolite, in the venous and arterial fetal cord blood was within the expected therapeutic range for adults. The clinical signs and a biomarker of essential fatty acid deficiency, namely the ratio of 20:3 [n-9] to 20:4 [n-6] fatty acids, were closely monitored throughout her pregnancy. Despite her extremely low fat diet, the levels of essential fatty acids measured in the mother and in the fetal blood immediately postpartum were normal. Normal essential fatty acid levels may have been achieved by the topical application of sunflower oil. CONCLUSIONS: An extremely low fat diet in combination with topical sunflower oil and gemfibrozil administration was safely implemented in pregnancy associated with the severe hypertriglyceridemia of lipoprotein lipase deficiency.

Association of bioavailable, free, and total testosterone with insulin resistance: influence of sex hormone-binding globulin and body fat.

OBJECTIVE: Previous reports of an association between low testosterone levels and diabetes risk were often confounded by covariation of sex hormone-binding globulin (SHBG) and testosterone measurements. Measurements of bioavailable and free testosterone, more reliable indexes of biologically active testosterone, were examined for their associations with markers of insulin resistance and body fat measures in 221 middle-aged nondiabetic men. RESEARCH DESIGN AND METHODS: Bioavailable and free testosterone were calculated from the concentrations of total testosterone, SHBG, and albumin, and they were not significantly correlated with SHBG (r = 0.07-0.1). In contrast, total testosterone correlated significantly with SHBG (r = 0.63). We evaluated the relationship between these measures of circulating testosterone and markers for insulin resistance (i.e., fasting insulin, C-peptide, and homeostasis model assessment for insulin resistance [HOMA-IR]) as well as total body fat (assessed by dual-energy X-ray absorptiometry [DEXA]) and abdominal fat distribution (assessed by single-slice computed tomography [CT]). RESULTS: Bioavailable, free, and total testosterone and SHBG all correlated significantly with fasting insulin (age-adjusted r = -0.15 [P = 0.03], -0.14 [P = 0.03], -0.32 [P < 0.0001], and -0.38 [P < 0.0001], respectively), fasting C-peptide (r = -0.18 [P = 0.009] to -0.41 [P < 0.0001]), HOMA-IR (r = -0.15 [P = 0.03] to - 0.39 [P < 0.0001]), and body fat measures (r = -0.17 [P = 0.008] to -0.44 [P < 0.0001]). Only SHBG and total testosterone were significantly associated with fasting glucose (r = -0.20 [P = 0.003] to -0.21 [P = 0.002]). In multivariate analysis, bioavailable or free testosterone was significantly and inversely associated with insulin, C-peptide, and HOMA-IR, but this was not independent of total body or abdominal fat. SHBG was a significant determinant of insulin, C-peptide, and HOMA-IR, independent of body fat. The associations between total testosterone and insulin resistance were confounded by SHBG. CONCLUSIONS: The inverse association between testosterone and insulin resistance, independent of SHBG, was mediated through body fat.