The apolipoprotein E ε4 (APOE ε4) is the main known genetic risk factor for Alzheimer's disease. Genetic assessments in combination with other diagnostic tools, such as neuroimaging, have the ...potential to facilitate early diagnosis. In this large-scale functional MRI (fMRI) study, we have contrasted 30 APOE ε4 carriers (age range: 49–74 years; 19 females), of which 10 were homozygous for the ε4 allele, and 30 non-carriers with regard to brain activity during a semantic categorization task. Test groups were closely matched for sex, age and education. Critically, both groups were cognitively intact and thus symptom-free of Alzheimer's disease. APOE ε4 carriers showed reduced task-related responses in the left inferior parietal cortex, and bilaterally in the anterior cingulate region. A dose-related response was observed in the parietal area such that diminution was most pronounced in homozygous compared with heterozygous carriers. In addition, contrasts of processing novel versus familiar items revealed an abnormal response in the right hippocampus in the APOE ε4 group, mainly expressed as diminished sensitivity to the relative novelty of stimuli. Collectively, these findings indicate that genetic risk translates into reduced functional brain activity, in regions pertinent to Alzheimer's disease, well before alterations can be detected at the behavioural level.
Increased Glucose Levels Are Associated With Episodic Memory in Nondiabetic Women
Olov Rolandsson 1 ,
Anna Backeström 1 ,
Sture Eriksson 2 ,
Göran Hallmans 3 and
Lars-Göran Nilsson 4
1 Department of ...Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden
2 Department of Community Medicine and Rehabilitation, Geriatric Medicine, Umeå University, Umeå, Sweden
3 Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden
4 Department of Psychology, Stockholm University, Stockholm, Sweden
Address correspondence and reprint requests to Dr. Olov Rolandsson, Family Medicine, Department of Public Health and Clinical
Medicine, NUS, S-901 85 Umeå, Sweden. E-mail: olov.rolandsson{at}fammed.umu.se
Abstract
OBJECTIVE —Patients with type 2 diabetes have an increased risk of a reduction in cognitive function. We investigated the hypothesis
that plasma glucose is associated with a reduction in episodic and/or semantic memory already in nondiabetic subjects.
RESEARCH DESIGN AND METHODS —We linked two large population-based datasets in Sweden: the Betula study, in which a random sample from the population aged
35–85 years was investigated for cognitive function, including episodic and semantic memory; and the Västerbotten Intervention
Program, a health survey with subjects aged 40, 50, and 60 years, that includes measuring of fasting and 2-h plasma glucose,
along with other risk factors for diabetes and cardiovascular disease. We identified 411 (179 men and 232 women, mean age
50.6 ± 8.0 years) nondiabetic subjects, free from dementia, who had participated in the two surveys within 6 months.
RESULTS —Women had better episodic (score 7.37 ± 1.42) and semantic memory (score 16.05 ± 2.76) than men (score 6.59 ± 1.29 and 15.15
± 2.92, respectively, P < 0.001 for both). In an adjusted multivariate model, fasting plasma glucose (fPG) and 2-h plasma glucose (2hPG) were significantly
negatively associated with episodic memory (fPG: B −0.198, SE 0.068, β −0.209, P = 0.004; and 2hPG: B −0.061, SE 0.031, β −0.148, P = 0.048, respectively) in women but not in men. The association was not found in relation to semantic memory.
CONCLUSIONS —We conclude that an increase in plasma glucose is associated with impairment in episodic memory in women. This could be explained
by a negative effect on the hippocampus caused by raised plasma glucose levels.
2hPG, 2-hour plasma glucose
CES-D, the Center for Epidemiologic Studies Depression Scale
fPG, fasting plasma glucose
IFG, impaired fasting glucose
IGT, impaired glucose tolerance
MMSE, Mini Mental State Examination
OGTT, oral glucose tolerance test
VIF, variance inflation factor
VIP, Västerbotten Intervention Program
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 31 October 2007. DOI: 10.2337/db07-1215.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted October 25, 2007.
Received August 30, 2007.
DIABETES
The objective was to examine whether aspects of social relationships in old age are associated with all-cause dementia and Alzheimer's disease (AD).
We studied 1,715 older adults (≥ 65 years) who ...were dementia-free at baseline over a period of up to 16 years. Data on living status, contact/visit frequency, satisfaction with contact frequency, and having/not having a close friend were analyzed using Cox proportional hazards regressions with all-cause dementia or AD as the dependent variable. To control for reverse causality and to identify potential long-term effects, we additionally performed analyses with delayed entry.
We identified 373 incident cases of dementia (207 with AD) during follow-up. The variable visiting/visits from friends was associated with reduced risk of all-cause dementia. Further, a higher value on the relationships index (sum of all variables) was associated with reduced risk of all-cause dementia and AD. However, in analyses with delayed entry, restricted to participants with a survival time of three years or more, none of the social relationship variables was associated with all-cause dementia or AD.
The results indicate that certain aspects of social relationships are associated with incident dementia or AD, but also that these associations may reflect reverse causality. Future studies aimed at identifying other factors of a person's social life that may have the potential to postpone dementia should consider the effects of reverse causality.
The impact of stressful life events as a risk factor of dementia diseases is inconclusive. We sought to determine whether stressful negative life events are associated with incidental dementia in a ...population-based study with long-term follow-up. We also tested the hypothesis that the occurrence of positive life events could mitigate or overcome the possible adverse effects of negative life events on dementia conversion.
The study involved 2,462 dementia-free participants aged 55 years and older. Information on life events was ascertained at baseline from a comprehensive Life Event Inventory, which included 56 questions about specific life events. For each life event, the emotional impact (both positive and negative) and emotional adjustment were asked for.
During follow-up, 423 participants developed dementia; of these, 240 developed Alzheimer's disease (AD). Cox regression analysis showed no association between the total number of negative life events and the incidence of dementia when adjusted solely for age and gender (hazard ratio = 0.97, 95% CI = 0.92-1.02), or with multiple adjustments for a range of covariates (hazard ratio = 0.96, 95% CI = 0.91-1.01). Similarly, neither emotional impact nor emotional adjustment to these life events was associated with incident dementia. A separate analysis of AD did not alter the results.
The result of this population-based study finds no association between negative or positive life events and dementia. Accordingly, our results reject the hypothesis that stressful life events trigger the onset of dementia diseases.
Compared to high-flux dialysis membranes, novel medium cut-off (MCO) membranes show greater permeability for larger middle molecules.
In two prospective, open-label, controlled, randomized, crossover ...pilot studies, 39 prevalent hemodialysis (HD) patients were studied in four dialysis treatments as follows: study 1, three MCO prototype dialyzers (AA, BB and CC with increasing permeability) and one high-flux dialyzer in HD; and study 2, two MCO prototype dialyzers (AA and BB) in HD and high-flux dialyzers in HD and hemodiafiltration (HDF). Primary outcome was lambda free light chain (λFLC) overall clearance. Secondary outcomes included overall clearances and pre-to-post-reduction ratios of middle and small molecules, and safety of MCO HD treatments.
MCO HD provided greater λFLC overall clearance least square mean (standard error) as follows: study 1: MCO AA 8.5 (0.54), MCO BB 11.3 (0.51), MCO CC 15.0 (0.53) versus high-flux HD 3.6 (0.51) mL/min; study 2: MCO AA 10.0 (0.58), MCO BB 12.5 (0.57) versus high-flux HD 4.4 (0.57) and HDF 6.2 (0.58) mL/min. Differences between MCO and high-flux dialyzers were consistently significant in mixed model analysis (each P < 0.001). Reduction ratios of λFLC were greater for MCO. Clearances of α1-microglobulin, complement factor D, kappa FLC (κFLC) and myoglobin were generally greater with MCO than with high-flux HD and similar to or greater than clearances with HDF. Albumin loss was moderate with MCO, but greater than with high-flux HD and HDF.
MCO HD removes a wide range of middle molecules more effectively than high-flux HD and even exceeds the performance of high-volume HDF for large solutes, particularly λFLC.
Mousavi‐Nasab, S.‐M.‐H., Kormi‐Nouri, R., Sundström, A. & Nilsson, L.‐G. (2012). The effects of marital status on episodic and semantic memory in healthy middle‐aged and old individuals. Scandinavian ...Journal of Psychology 53, 1–8.
The present study examined the influences of marital status on different episodic and semantic memory tasks. A total of 1882 adult men and women participated in a longitudinal project (Betula) on memory, health and aging. The participants were grouped into two age cohorts, 35–60 and 65–85, and studied over a period of 5 years. Episodic memory tasks concerned recognition and recall, whereas semantic memory tasks concerned knowledge and fluency. The results showed, after controlling for education, some diseases, chronological age and leisure activity as covariates, that there were significant differences between married and single individuals in episodic memory, but not in semantic memory. Married people showed significantly better memory performances than singles in both subsystems of episodic memory, that is, recall and recognition. Also, the rate of decline in episodic memory was significantly larger for singles and widowed than other groups over the 5‐year time period in both age groups. The findings demonstrate that the positive relation found between marriage and health can be extended to the relation between marriage and cognitive performance. This effect might be explained by the role played by cognitive stimulation in memory and cognition.
Abstract Cross-sectional neuroimaging studies suggest that hippocampal and prefrontal cortex functions underlie individual differences in memory ability in older individuals, but it is unclear how ...individual differences in cognitive ability in youth contribute to cognitive and neuroimaging measures in older age. Here, we investigated the relative influences of midlife memory ability and age-related memory change on memory-related BOLD-signal variability at one time point, using a sample from a longitudinal population-based aging study (N = 203, aged 55–80 years). Hierarchical regression analyses showed that midlife memory ability, assessed 15–20 years earlier, explained at least as much variance as memory change in clusters in the left inferior prefrontal cortex and the bilateral hippocampus, during memory encoding. Furthermore, memory change estimates demonstrated higher sensitivity than current memory levels in identifying distinct frontal regions where activity was selectively related to age-related memory change, as opposed to midlife memory. These findings highlight challenges in interpreting individual differences in neurocognitive measures as age-related changes in the absence of longitudinal data and also demonstrate the improved sensitivity of longitudinal measures.
The study examined the extent to which time-related gains in cognitive performance, so-called Flynn effects, generalize across sub-factors of episodic memory (recall and recognition) and semantic ...memory (knowledge and fluency). We conducted time-sequential analyses of data drawn from the Betula prospective cohort study, involving four age-matched samples (35–80 years;
N
=
2996) tested on the same battery of memory tasks on either of four occasions (1989, 1995, 1999, and 2004). The results demonstrate substantial time-related improvements on recall and recognition as well as on fluency and knowledge, with a trend of larger gains on semantic as compared with episodic memory Rönnlund, M., & Nilsson, L. -G. (2008). The magnitude, generality, and determinants of Flynn effects on forms of declarative memory: Time-sequential analyses of data from a Swedish cohort study.
Intelligence, but highly similar gains across the sub-factors. Finally, the association with markers of environmental change was similar, with evidence that historical increases in quantity of schooling was a main driving force behind the gains, both on the episodic and semantic sub-factors. The results obtained are discussed in terms of brain regions involved.
The majority of bicarbonate based dialysis fluids are acidified with acetate. Citrate, a well known anticoagulant and antioxidant, has been suggested as a biocompatible alternative. The objective of ...this study was to evaluate short term safety and biocompatibility of a citrate containing acetate-free dialysis fluid.
Twenty four (24) patients on maintenance dialysis three times per week, 13 on on-line hemodiafiltration (HDF) and 11 on hemodialysis (HD), were randomly assigned to start with either citrate dialysis fluid (1 mM citrate, 1.5 mM calcium) or control fluid (3 mM acetate, 1.5 mM calcium) in an open-labeled cross-over trial (6 + 6 weeks with 8 treatments wash-out in between). Twenty (20) patients, 11 on HDF and 9 on HD were included in the analyses. Main objective was short term safety assessed by acid-base status, plasma ionized calcium and parathyroid hormone (PTH). In addition, biocompatibility was assessed by markers of inflammation (pentraxin 3 (PTX-3), CRP, IL-6, TNF-α and IL-1β) and thrombogenicity (activated partial thromboplastin time (APTT) and visual clotting scores).
No differences dependent on randomization order or treatment mode (HD vs. HDF) were detected. Citrate in the dialysis fluid reduced the intra-dialytic shift in pH (+0.04 week 6 vs. +0.06 week 0, p = 0.046) and base excess (+3.9 mM week 6 vs. +5.6 mM week 0, p = 0.006) over the study period. Using the same calcium concentration (1.5 mM), citrate dialysis fluid resulted in lower post-dialysis plasma ionized calcium level (1.10 mM vs. 1.27 mM for control, p < 0.0001) and higher post-dialysis PTH level (28.8 pM vs. 14.7 pM for control, p < 0.0001) while pre-dialysis levels were unaffected. Citrate reduced intra-dialytic induction of PTX-3 (+1.1 ng/ml vs. +1.4 ng/ml for control, p = 0.04) but had no effect on other markers of inflammation or oxidative stress. Citrate reduced visual clotting in the arterial air chamber during HDF (1.0 vs. 1.8 for control, p = 0.03) and caused an intra-dialytic increase in APTT (+6.8 s, p = 0.003) without affecting post-dialysis values compared to control.
During this small short term study citrate dialysis fluid was apparently safe to use in HD and on-line HDF treatments. Indications of reduced treatment-induced inflammation and thrombogenicity suggest citrate as a biocompatible alternative to acetate in dialysis fluid. However, the results need to be confirmed in long term studies.
ISRCTN28536511.
Despite the wealth of commercially available antibodies to human proteins, research is often hindered by their inconsistent validation, their poor performance and the inadequate coverage of the ...proteome. These issues could be addressed by systematic, genome-wide efforts to generate and validate renewable protein binders. We report a multicenter study to assess the potential of hybridoma and phage-display technologies in a coordinated large-scale antibody generation and validation effort. We produced over 1,000 antibodies targeting 20 SH2 domain proteins and evaluated them for potency and specificity by enzyme-linked immunosorbent assay (ELISA), protein microarray and surface plasmon resonance (SPR). We also tested selected antibodies in immunoprecipitation, immunoblotting and immunofluorescence assays. Our results show that high-affinity, high-specificity renewable antibodies generated by different technologies can be produced quickly and efficiently. We believe that this work serves as a foundation and template for future larger-scale studies to create renewable protein binders.
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