Omega-3 fatty acids and cognitive decline: modulation by ApoEε4 allele and depression

Long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may slow cognitive decline. The ε4 allele of the ApolipoproteinE (ApoE), the main genetic risk factor for Alzheimer's disease, and depressive symptoms, which are frequently associated with cognitive impairment in older persons, may modify this relationship. We estimated the associations between EPA and DHA plasma levels and subsequent cognitive decline over 7 years, taking into account ApoE-ε4 status and depressive symptoms, in a prospective population-based cohort. Participants (≥ 65 years, n = 1,228 nondemented at baseline) were evaluated at least once over three follow-up visits using four cognitive tests. Plasma EPA was associated with slower decline on Benton Visual Retention Test (BVRT) performances in ApoE-ε4 carriers, or in subjects with high depressive symptoms at baseline. Plasma DHA was associated with slower decline on BVRT performances in ApoE-ε4 carriers only. EPA and DHA may contribute to delaying decline in visual working memory in ApoE-ε4 carriers. In older depressed subjects, EPA, but not DHA, may slow cognitive decline.     

Does aspirin or other NSAIDs reduce the risk of cognitive decline in elderly persons? Results from a population-based study

OBJECTIVE: To investigate the protective effect of NSAIDs and aspirin separately on cognitive decline in elderly subjects, controlling for consistent use of these agents over a prolonged period of time. METHODS: The study sample consisted of 1007 subjects, drawn from a population-based random sample of elderly individuals, 62-85 years old, who participated in a 3-year follow-up study. From this sample subjects were selected, who did use NSAIDs and completed all cognitive tests at both measurements (n=137), and subjects who did not use NSAIDs and completed all cognitive tests (n=475). Cognitive tests included the Mini-Mental State Examination (MMSE), tests for episodic memory (Auditory Verbal Learning Test) and information processing speed (coding task). Cognitive decline was computed using Edwards-Nunnally method. Multiple logistic regression analyses were performed to examine the association between NSAID (with and without aspirin) and decline in cognitive performance. Besides, the interaction of NSAIDs with age on cognitive decline was determined. RESULTS: The relative risk estimates of decline in episodic memory (immediate recall) adjusted for age, gender, education, baseline MMSE, vascular diseases, diabetes mellitus and (rheumatoid) arthritis for aspirin users only was more than three times reduced (OR: 0.30, 95% CI: 0.09-0.82). The odds ratio for decline in memory of NSAID use without aspirin, adjusted for age, gender, education, baseline MMSE, vascular diseases, diabetes mellitus and (rheumatoid) arthritis was not significant (OR: 1.00, 95% CI: 0.39-2.93). The effect of aspirin was significant only in persons of 75 years and over (OR: 0.10, 95% CI: 0.01-0.81), not in subjects younger than 75 years (OR: 0.52, 95% CI: 0.14-1.96). NSAIDs did not have benefit on information processing speed. In 92% of aspirin users a low dose of 100mg daily or less was used. CONCLUSION: Low-dose aspirin might be protective for decline in memory in individuals of 75 years and over. The benefit of a low-dose aspirin does not support an anti-inflammatory effect, but suggests an antiplatelet effect. Therefore, a possible protective effect of low-dose aspirin on cognitive decline is likely only in subjects with aspirin use over a prolonged period of time.     

A coding variant in CR1 interacts with APOE-ε4 to influence cognitive decline

Complement receptor 1 (CR1) is an Alzheimer's disease (AD) susceptibility locus that also influences AD-related traits such as episodic memory decline and neuritic amyloid plaque deposition. We implemented a functional fine-mapping approach, leveraging intermediate phenotypes to identify functional variant(s) within the CR1 locus. Using 1709 subjects (697 deceased) from the Religious Orders Study and the Rush Memory and Aging Project, we tested 41 single-nucleotide polymorphisms (SNPs) within the linkage disequilibrium block containing the published CR1 AD SNP (rs6656401) for associations with episodic memory decline, and then examined the functional consequences of the top result. We report that a coding variant in the LHR-D (long homologous repeat D) region of the CR1 gene, rs4844609 (Ser1610Thr, minor allele frequency = 0.02), is associated with episodic memory decline and accounts for the known effect of the index SNP rs6656401 (D' = 1, r(2)= 0.084) on this trait. Further, we demonstrate that the coding variant's effect is largely dependent on an interaction with APOE-ε4 and mediated by an increased burden of AD-related neuropathology. Finally, in our data, this coding variant is also associated with AD susceptibility (joint odds ratio = 1.4). Taken together, our analyses identify a CR1 coding variant that influences episodic memory decline; it is a variant known to alter the conformation of CR1 and points to LHR-D as the functional domain within the CR1 protein that mediates the effect on memory decline. We thus implicate C1q and MBL, which bind to LHR-D, as likely targets of the variant's effect and suggest that CR1 may be an important intermediate in the clearance of Aβ42 particles by C1q.     

Lack of association between PICALM rs3851179 polymorphism and Alzheimer's disease in Chinese population and APOEε4-negative subgroup

Recently, the association between PICALM rs3851179 polymorphism and Alzheimer's disease (AD) was investigated in the Chinese population by 3 independent studies. However, both allele and genotype tests failed to reveal any association. The association was identified only in the APOEε4-negative subgroup. We think that the failure to replicate the association may be because of the relatively small sample size. In this research, we reinvestigated the association using all the samples from these 3 studies (n = 2486, and 1202 cases and 1284 control subjects). We failed to replicate this association between the rs3851179 polymorphism and AD in all samples and the APOEε4-negative subgroup. Our results indicate that rs3851179 may not be an AD susceptibility locus in the Chinese population and the APOEε4-negative subgroup.     

The effect of APOE genotype on brain levels of oxysterols in young and old human APOE ε2, ε3 and ε4 knock-in mice

Despite apolipoprotein E's important role in cholesterol transport and metabolism in the brain as well as its influence on Alzheimer's disease, the impact of the human APOE genotype on cholesterol metabolism in brain has not been fully examined. This study was carried out to investigate APOE genotype effects on oxysterols measured. In this study the measurement of cholesterol and several oxysterols in the brains of human APOE ε2, ε3 and ε4 knock-in mice at 8 weeks and 1 year of age using gas chromatography mass spectrometry (GC–MS) demonstrated no APOE genotype or age effect on total brain cholesterol and the oxysterol 24-hydroxycholesterol. The level of 27-hydroxycholesterol was elevated in 1 year old animals for all APOE genotypes. Interestingly, lathosterol an indicator of cholesterol synthesis was significantly reduced in the 1 year old animals for all APOE genotypes. APOE ε4 expressing mice exhibited statistically lower levels of lathosterol compared to APOE ε2 in both the young and old mice. Oxidized cholesterol metabolites were significantly lower in APOE ε2 mice compared to other genotypes at 8 weeks old. Although minimal differences were observed between APOE E3 and E4 knock-in (KI) mice, these findings indicate that there are some clear APOE genotype specific effects on brain cholesterol synthesis and associated metabolic pathways, particularly in APOE ε2 KI mice.     

Effects of APOE ɛ4 on brain amyloid,lacunar infarcts,and white matter lesions: a study among patients with subcortical vascular cognitive impairment

The relationship between the apolipoprotein E ?4 allele (APOE4) and factors associated with vascular cognitive impairment (VCI) is unclear. We aimed to examine the effects of APOE4 on brain amyloid beta using Pittsburg compound B (PiB) and subcortical cerebrovascular disease, as assessed by lacunes and white matter hyperintensities (WMH) in subcortical VCI (SVCI) patients. We recruited 230 subjects with normal cognition, 111 subjects with cognitive impairment due to clinically defined Alzheimer’s disease (ADCI), and 134 subjects with clinically defined SVCI. A PiB retention ratio greater than 1.5 was considered to be PiB positive. Logistic regression analysis was performed to investigate whether APOE4 increased the risk for each cognitive impairment group. Multiple linear regression analysis was performed to investigate whether APOE4 was associated with brain amyloid beta, lacunes, and WMH. APOE4 did not increase the risk of PiB(−) SVCI (odds ratio [OR], 1.50; 95% confidence interval [CI], 0.79–2.84), whereas APOE4 increased the risk of PiB(+) SVCI (OR, 4.52; 95% CI, 1.70–11.97) and PiB(+) ADCI (odds ratio, 4.84; 95% CI, 2.54–7.91). In SVCI patients, APOE4 was positively associated with PiB retention ratio, whereas APOE4 was not associated with the number of lacunes or with WMH volume. Our results suggest that amyloid beta burden can occur in patients with and without subcortical cerebrovascular disease, and that it is associated with APOE4. However APOE4 might be independent of subcortical cerebrovascular disease.     

Considerable variation of trough β-lactam concentrations in older adults hospitalized with infection—a prospective observational study

In older adults, few studies confirm that adequate concentrations of antibiotics are achieved using current dosage regimens of intravenous β-lactam antibiotics. Our objective was to investigate trough concentrations of cefotaxime, meropenem, and piperacillin in older adults hospitalized with infection. We included 102 patients above 70 years of age. Total trough antibiotic concentrations were measured and related to suggested target intervals. Information on antibiotic dose, patient characteristics, and 28-day outcomes were collected from medical records and regression models were fitted. Trough concentrations for all three antibiotics exhibited considerable variation. Mean total trough concentrations for cefotaxime, meropenem, and piperacillin were 6.5 mg/L (range 0–44), 3.4 mg/L (range 0–11), and 30.2 mg/L (range 1.2–131), respectively. When a target range of non-species-related breakpoint ? 5× non-species-related breakpoint was applied, only 36% of patients had both values within the target range. Regression models revealed that severe sepsis was associated with varying concentration levels and increasing age and diminishing kidney function with high concentration levels. The study was not powered to demonstrate consequences in clinical outcomes. Conclusively, in older adults treated with cefotaxime, meropenem, or piperacillin-tazobactam, trough antibiotic concentrations varied considerably. Better predictors to guide dosing regimens of β-lactam antibiotics or increased use of therapeutic drug monitoring are potential ways to address such variations.     

The role of lipoproteins and inflammation in cognitive decline: Do they interact?

The aim of this study was to examine the associations between high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides, and cognition and focus on the modifying effect of inflammation. Data were collected in the population-based Longitudinal Aging Study Amsterdam and analyzed with mixed linear models. The sample comprised 1003 persons ≥ 65 years with cognitive data on at least 2 occasions over 6 years of follow-up. Cognition was measured with the Mini-Mental State Examination (general cognition), Auditory Verbal Learning Test (memory), and Coding Task (information processing speed). We found an independent association between high HDL cholesterol and better memory performance. In addition, low LDL cholesterol was predictive of worse general cognitive performance and faster decline on information processing speed. Furthermore, a significant modifying effect of inflammation (C-reactive protein, α-antichymotrypsin) was found. A negative additive effect of low LDL cholesterol and high inflammation was found on general cognition and memory performance. Also, high triglycerides were associated with lower memory performance in those with high inflammation. Thus, a combination of these factors may be used as markers of prolonged lower cognitive functioning.     

PPARG Pro12Ala genotype and risk of cognitive decline in elders? Maybe with diabetes

The Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma (PPARG; NCBI dbSNP rs1801282) has been associated with preservation of cognitive function, decreased risk of diabetes, and increased risk of obesity. We attempted to replicate these associations, testing cognitive function and lifetime cognitive change in 519 participants who took the same cognitive test at ages 11 and 79 years. Scores were also available for other cognitive tests at age 79 years, along with history of diabetes, current Body Mass Index (BMI), and other disease and demographic variables. Pro12Ala carrier status was not directly associated with diabetes history or BMI. In carriers who contracted diabetes despite carrying the protective allele, cognitive decline as measured by one test was significantly greater than in other groups. Only six individuals fell into this group; the other cognitive tests did not show this effect. This sample did not replicate the direct association of the PPARG Pro12Ala allele with diabetes status or preserved cognitive function. The data did suggest that risk of cognitive decline is greater when Pro12Ala carriers contract diabetes.     

Transmission of hepatitis B in Hamburg,Germany, 1998–2002: a prospective,population-based study

To study the pattern of transmission of HBV in a large urban community, an in-depth prospective study was performed in Hamburg between 1 January 1998 and 31 December 2002. In total, 524 patients were classified as hepatitis B cases according to the case definition of the Robert Koch Institute, comprising 197 foreign-born and 327 German-born persons. The principal risk factor was parenteral drug use, with 17.7% (n=93/524) of all documented cases of hepatitis B, followed by immigration as refugees (13.9%; n=73). Of all 524 cases, 72 (13.7%) were associated with heterosexual (n=41) or homosexual (n=31) transmission. Household contacts of HBV carriers or of patients with acute infectious disease contributed to 9.0% of the cases (n=47). Medical procedures were most probably the source in 7.4% (n=39), although only 3.2% (n=17) of all patients were health-care workers. In multivariate analysis of household contacts, male–male sexual activity was found to be the greatest risk factor for acquiring an acute HBV infection, followed by asylum-seeking status and the number of contacts. The incidence was 3.5-fold higher among foreign-born persons (16.1 per 100,000) than among German-born individuals (4.5 per 100,000) suggesting that a targeted intervention in this population group is a public-health need. The current national policy of vaccination in defined age groups should be extended to the immunization of all children of foreign-born parents as well as the screening and immunisation of susceptible foreign-born adults.     

Do cognitive models help in predicting the severity of posttraumatic stress disorder, phobia, and depression after motor vehicle accidents? A prospective longitudinal study

The study investigated the power of theoretically derived cognitive variables to predict posttraumatic stress disorder (PTSD), travel phobia, and depression following injury in a motor vehicle accident (MVA). MVA survivors (N = 147) were assessed at the emergency department on the day of their accident and 2 weeks, 1 month, 3 months, and 6 months later. Diagnoses were established with the Structured Clinical Interview for DSM-IV. Predictors included initial symptom severities; variables established as predictors of PTSD in E. J. Ozer, S. R. Best, T. L. Lipsey, and D. S. Weiss's (2003) meta-analysis; and variables derived from cognitive models of PTSD, phobia, and depression. Results of nonparametric multiple regression analyses showed that the cognitive variables predicted subsequent PTSD and depression severities over and above what could be predicted from initial symptom levels. They also showed greater predictive power than the established predictors, although the latter showed similar effect sizes as in the meta-analysis. In addition, the predictors derived from cognitive models of PTSD and depression were disorder-specific. The results support the role of cognitive factors in the maintenance of emotional disorders following trauma.     

Neuropsychological profile of Alzheimer’s disease in women: moderate and moderately severe cognitive decline

Summary Introduction: Alzheimers disease (AD) is characterised by progressive cognitive and functional decline. There is evidence that AD is more prevalent in women. This study aims at identifying the clinical and sociodemographic variables associated with the cognitive functions and the pattern of decline in women with moderate to moderately severe AD.Methods: Cross-sectional observational study of 165 women with dementia of the AD type according to NINCDS-ADRDA criteria. The cognitive functions were assessed using the Cambridge Cognitive Examination (CAMCOG). The sociodemographic and clinical data were collected from the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX) interview, and the Neuropsychiatric Inventory (NPI) was administrated to the caregiver.Results: The number of years of schooling and the score on the CAMDEX depression scale were the variables associated with the CAMCOG score. The effect of these variables was not homogenous for all the CAMCOG subtests.Conclusions: The number of years of schooling and the presence of depressive symptomatology influence the results of the neuropsychological exploration, but the effect is moderate and not homogenous for all the CAMCOG subtests. The differences in cognitive profile between moderate and moderately severe are characterised by a greater effect on temporal orientation, calculation and perception.     

Spirituality,satisfaction with life and health-related behavior of older residents of long-term care institutions—a pilot study

Spirituality and satisfaction with life are psychological factors related to health behavior. The aim of the study was to determine whether satisfaction with life acts as a mediator in the relationship between the spirituality of residents of long-term care institutions and their health-related behavior. A total of 102 people aged 60–99 were examined. It was found that satisfaction with life played a mediating role in the relationship between spirituality and health behavior. The study addresses the gap in knowledge regarding institutionalized older adults, exploring the role of spirituality and satisfaction with life on lifestyle in nursing home settings.     

Coagulation and inflammation in scrub typhus and murine typhus—a prospective comparative study from Laos

Scrub typhus (caused by Orientia tsutsugamushi) and murine typhus (caused by Rickettsia typhi) cause up to 28% of febrile episodes in Thailand and Laos. The current understanding of coagulation and inflammation in the pathogenesis of these clinically very similar vasculotropic diseases is limited. This study compared human in vivo changes in 15 coagulation, inflammation and endothelial activation markers in prospectively collected admission and follow-up samples of 121 patients (55 scrub typhus, 55 murine typhus, and 11 typhus-like illness) and 51 healthy controls from Laos. As compared with controls, all but one of the markers assessed were significantly affected in typhus patients; however, the activation patterns differed significantly between scrub and murine typhus patients. The levels of markers of coagulation activation and all inflammatory cytokines, except for interleukin-12, were significantly higher in patients with scrub typhus than in those with murine typhus. In patients with murine typhus, however, the levels of endothelium-derived markers were significantly higher. Anticoagulant factors were inhibited in both typhus patient groups. This is the first study demonstrating that, in scrub typhus, in vivo coagulation activation is prominent and is related to a strong proinflammatory response, whereas in murine typhus, changes in coagulant and fibrinolytic pathways are suggestive of endothelial cell perturbation. These data suggest that, although late-stage endothelial infection is common in both diseases, the in vivo pathogenic mechanisms of R. typhi and O. tsutsugamushi could differ in the early phase of infection and may contribute to disease differentiation.     

ApoE ε2/ε3/ε4 polymorphism,ApoC-III/ApoE ratio and metabolic syndrome

Triglyceride-rich lipoproteins contain both apolipoproteins E (ApoE) and C-III (ApoC-III), which show opposite functional properties. The relationships between the ApoE (ε2/ε3/ε4) gene polymorphism and ApoC-III/ApoE ratio has never been investigated. A large population (n=552) of cardiovascular patients, without diabetes and/or lipid-lowering therapy, with or without metabolic syndrome (MetSyn), was genotyped for ε2/ε3/ε4 polymorphism and their ApoCIII/ApoE ratio was evaluated. A second group of patients (n=76) with peripheral artery disease was also genotyped and their ApoC-III/ApoE ratios were measured in HDL and non-HDL fractions. Subjects with E2 had higher and E4 carriers lower TG,ApoE and ApoC-III levels, respectively. The ApoCIII/ ApoE ratio showed an opposite trend, gradually increasing from E2/E2 to E4/E4 subjects. MetSyn patients also had an elevated ApoC-III/ApoE ratio and E4 carriers were more frequent in MetSyn patients (OR 2.08 with a 95%CI 1.22–3.5). The distribution of ApoC-III/ApoE ratio was confirmed also in the second group, with lower values in E2/E3 and higher in E3/E4 subjects. Similar results were obtained for the concentrations measured in non-HDL fractions, but not in the HDL fractions. ApoE ε2/ε/ε4 gene polymorphism is a determinant of the relative proportion of apolipoprotein C-III to E. Carriers of the unfavourable E4 allele present the highest ApoCIII/ApoE ratio and are twofold more frequent among individuals affected by MetSyn. These authors contributed equally to the work     

Impact of maternal depression on perinatal outcomes in hospitalized women—a prospective study

Archives of Women's Mental Health - Scarce data exists regarding the prevalence of antenatal depression in hospitalized pregnant women, and its effect on perinatal outcome. We aimed to estimate...