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Stephanie Bolton,1 Rachel Gair,2 Lars-Göran Nilsson,3 Michael Matthews,1 Louanne Stewart,1 Natasha McCullagh1 1Renal Unit, Antrim Area Hospital, Northern Health and Social Care Trust, Northern Ireland, UK; 2UK Renal Registry, Bristol, UK; 3Baxter International Inc., Lund, SwedenCorrespondence: Stephanie BoltonRenal Unit, Antrim Area Hospital, Northern Health and Social Care Trust, Northern Ireland, UKEmail Stephanie.Bolton@northerntrust.hscni.netIntroduction: Most people on hemodialysis (HD) report a high symptom burden. Fatigue and lack of energy are prominent, interfering with daily life and associated with poor outcome. Prolonged recovery time after each of the thrice weekly dialysis treatments is common. The impact of HD therapies, like expanded hemodialysis (HDx), on patient reported recovery time and symptom burden is unclear.Methods: A dialysis unit decided to perform regular assessments of patient-reported symptom burden, using the POS-S Renal Symptom questionnaire and the “Recovery time from last dialysis session” question as part of routine patient focused care. At a similar time, a clinical evidence-based decision was taken to switch the in-center dialysis cohort from regular high-flux dialysis membrane to medium cut-off (MCO) membrane, introducing HDx therapy.Results: Quarterly assessment of patient-reported symptom burden was well accepted. A sustained clinically relevant reduction in post-dialysis recovery time was observed following the therapy switch. In patients providing data up to 12 months (N = 58), median recovery time decreased from 210 min (IQR 7.5– 600) to 60 min (0– 210; p = 0.002) and 105 min (0– 180; p = 0.001) at 6 and 12 months, respectively. Thirty-six percent of individuals reported a recovery time longer than 360 minutes at the initial assessment, which decreased to 9% at 12 months. The POS-S Renal total symptom score showed a decrease at 6 months but no difference from baseline at 12 months. The “fatigue/lack of energy” symptom showed a sustained improvement; the percentage of participants scoring its impact as “severe” or “overwhelming” decreased from 28% at baseline to 16% at 12 months. Changes in other symptoms were more variable.Conclusion: Regular assessment of patient reported symptoms is feasible in routine dialysis practice and can help in evaluating the impact of clinical interventions. Observations suggest that HDx therapy may reduce post-dialysis recovery time and improve perceived fatigue level.Keywords: post-dialysis recovery time, symptom burden, fatigue, HDx therapy

We examined 5-year longitudinal changes in Tower of Hanoi (TOH) performance in a population-based sample of adults (35-85 years initially; n = 1480). An age-matched sample (n = 433) was included to estimate practice effects. The longitudinal age gradients differed substantially from the cross-sectional age gradients. This was the case even when practice effects, that were substantial in magnitude across the young/middle-aged groups, were controlled for. Instead of a continuous age-related deficit in performance from 35 and onwards, longitudinal data showed slowing of performance and increases of illegal moves past age 65. Cohort-related differences in educational attainment did not account for this discrepancy. Further analyses revealed a positive relation between practice-related gains and explicit memory of having performed the task at the first test occasion and a positive association between latent changes in TOH and Block Design, in line with cross-sectional findings. In conclusion, the results demonstrate a pattern of age-related changes indicating a late-onset decline of TOH performance and underscore the need to control for retest effects in longitudinal aging research. [ABSTRACT FROM AUTHOR]

Background: The epsilon4 allele of apolipoprotein E (APOE) and head injury are risk factors for dementia diseases, and may act synergistically to further increase the risk. The aim of this study was to examine the association between mild head injury, APOE and dementia.Methods: Data were obtained from the Betula prospective population-based study of aging, memory, and health. The study included 543 participants in the age range 40-85 years, free of dementia at baseline, who were followed up within a 5-year interval. Dementia was classified using DSM-IV criteria. Information on previous head injury was obtained through screening of the participants' answers to health questionnaires at baseline and at follow-up.Results: Subjects with head injury but without APOE epsilon4 had no increased risk of dementia. Subjects with APOE epsilon4 had an increased risk and those with both APOE epsilon4 and head injury had the highest risk of dementia (odds ratio = 5.2).Conclusions: APOE epsilon4 constitutes a risk factor for dementia, mild injury in isolation does not increase the risk, but head injury in combination with the APOE epsilon4 leads to increased risk of dementia. [ABSTRACT FROM AUTHOR]

Expanded hemodialysis (HDx), using medium cut-off membrane, is a novel therapy that effectively clears middle molecules (MMs). We aimed to compare HDx to hemodiafiltration (HDF) in an open randomized clinical study. Patients currently on HDF (age 18-80 years; on HDF >3 months) were randomized to switch to HDx (N = 21) or continue HDF (N = 22) with a 24-week follow-up. Pre- to post-dialysis reduction ratios (RR) and changes in pre-dialysis levels over time were evaluated for MMs and clinical biomarkers. Use of erythropoiesis-stimulating agents (ESAs) was assessed. HDx showed greater RR for YKL-40 while RR appeared similar between groups for beta 2 -microglobulin, FGF-23, and free light chains. Intradialytic changes in inflammatory biomarkers (IL-6, CRP, PTX3) did not differ between therapies. Changes from baseline to 12 and 24 weeks did not differ between groups for MMs, inflammatory markers, albumin, fibrinogen, hemoglobin, PTH, and phosphorus. Use of ESAs tended to decrease in HDx arm while remaining stable in HDF arm. HDx appeared safe with similar clinical effectiveness as HDF. With fewer requirements and resource needs, HDx provides an attractive alternative to HDF., (© 2021 Baxter HealthCare Corporation. Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf of International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Expanded hemodialysis (HDx) provides increased clearance of conventional and large middle molecules through innovative medium cutoff (MCO) membranes. However, there is a paucity of real-world data regarding the benefits and safety of HDx. This large observational study evaluated outcomes among patients in Colombia undergoing HDx at a extended dialysis clinical services provider. This was a prospective single cohort study of prevalent patients who were treated with HDx; baseline information was collected from the most recent data before patients were started on HDx. Patients were followed prospectively for 1 year for changes in serum albumin and other laboratory parameters compared with the baseline. Survival, hospitalization and safety were assessed from the start of HDx. A total of 1000 patients were invited to enroll; 992 patients met the inclusion criteria for data analysis and 638 patients completed the year of follow-up. Seventy-four (8%) patients died during 866 patient-years (PY) of follow-up; the mortality rate was 8.54 deaths/100 PY (95% confidence interval [CI], 6.8-10.7). There were 673 hospitalization events with a rate of 0.79 events/PY (95% CI, 0.73-0.85) with 6.91 hospital days/PY (95% CI, 6.74-7.09). The observed variability from baseline and maximum average change in mean serum albumin levels were -1.8% and -3.5%, respectively. No adverse events were related to the MCO membrane. HDx using an MCO membrane maintains stable serum albumin levels and is safe in terms of nonoccurrence of dialyzer related adverse events., (© 2020 The Authors. Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf of International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Background: Automated peritoneal dialysis (APD) is a growing PD modality but as with other home dialysis methods, the lack of monitoring of patients' adherence to prescriptions is a limitation with potential negative impact on clinical outcome parameters. Remote patient monitoring (RPM) allowing the clinical team to have access to dialysis data and adjust the treatment may overcome this limitation. The present study sought to determine clinical outcomes associated with RPM use in incident patients on APD therapy. Methods: A retrospective cohort study included 360 patients with a mean age of 57 years (diabetes 42.5%) initiating APD between 1 October 2016 and 30 June 2017 in 28 Baxter Renal Care Services (BRCS) units in Colombia. An RPM program was used in 65 (18%) of the patients (APD-RPM cohort), and 295 (82%) were treated with APD without RPM. Hospitalizations and hospital days were recorded over 1 year. Propensity score matching 1:1, yielding 63 individuals in each group, was used to evaluate the association of RPM exposure with numbers of hospitalizations and hospital days. Results: After propensity score matching, APD therapy with RPM ( n = 63) compared with APD-without RPM ( n = 63) was associated with significant reductions in hospitalization rate (0.36 fewer hospitalizations per patient-year; incidence rate ratio [IRR] of 0.61 [95% confidence interval (CI) 0.39 - 0.95]; p = 0.029) and hospitalization days (6.57 fewer days per patient-year; IRR 0.46 [95% CI 0.23 - 0.92]; p = 0.028). Conclusions: The use of RPM in APD patients is associated with lower hospitalization rates and fewer hospitalization days; RPM could constitute a tool for improvement of APD therapy., (Copyright © 2019 International Society for Peritoneal Dialysis.)

Objectives: To determine whether dementia could explain the association between poor olfactory performance and mortality risk within a decade-long follow-up period., Design: Prospective cohort study., Setting: Betula Study, Umeå, Sweden., Participants: A population-based sample of adult participants without dementia at baseline aged 40 to 90 (N = 1,774)., Measurements: Olfactory performance using the Scandinavian Odor-Identification Test (SOIT) and self-reported olfactory function; several social, cognitive, and medical risk factors at baseline; and incident dementia during the following decade., Results: Within the 10-year follow-up, 411 of 1,774 (23.2%) participants had died. In a Cox model, the association between higher SOIT score and lower mortality was significant (hazard ratio (HR) = 0.74 per point interval, 95% confidence interval (CI) = 0.71-0.77, P < .001). The effect was attenuated, but remained significant, after controlling for age, sex, education, and health-related and cognitive variables (HR = 0.92, 95% CI = 0.87-0.97, P = .001). The association between SOIT score and mortality was retained after controlling for dementia conversion before death (HR = 0.92, 95% CI = 0.87-0.97, P = .001). Similar results were obtained for self-reported olfactory dysfunction., Conclusion: Poor odor identification and poor self-reported olfactory function are associated with greater likelihood of future mortality. Dementia does not attenuate the association between olfactory loss and mortality, suggesting that olfactory loss might mark deteriorating health, irrespective of dementia., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

The complement cascade plays a role in synaptic pruning and synaptic plasticity, which seem to be involved in cognitive functions and psychiatric disorders. Genetic variants in the closely related CSMD1 and CSMD2 genes, which are implicated in complement regulation, are associated with schizophrenia. Since patients with schizophrenia often show cognitive impairments, we tested whether variants in CSMD1 and CSMD2 are also associated with cognitive functions per se. We took a discovery-replication approach, using well-characterized Scandinavian cohorts. A total of 1637 SNPs in CSMD1 and 206 SNPs in CSMD2 were tested for association with cognitive functions in the NCNG sample (Norwegian Cognitive NeuroGenetics; n=670). Replication testing of SNPs with p-value<0.001 (7 in CSMD1 and 3 in CSMD2) was carried out in the TOP sample (Thematically Organized Psychosis; n=1025) and the BETULA sample (Betula Longitudinal Study on aging, memory and dementia; n=1742). Finally, we conducted a meta-analysis of these SNPs using all three samples. The previously identified schizophrenia marker in CSMD1 (SNP rs10503253) was also included. The strongest association was observed between the CSMD1 SNP rs2740931 and performance in immediate episodic memory (p-value=5×10 -6 , minor allele A, MAF 0.48-0.49, negative direction of effect). This association reached the study-wide significance level (p⩽1.2×10 -5 ). SNP rs10503253 was not significantly associated with cognitive functions in our samples. In conclusion, we studied n=3437 individuals and found evidence that a variant in CSMD1 is associated with cognitive function. Additional studies of larger samples with cognitive phenotypes will be needed to further clarify the role of CSMD1 in cognitive phenotypes in health and disease., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

The objective of the present study was to examine relations between social network size and three cognitive abilities (episodic memory, semantic memory, visuospatial ability) in middle-aged adults. We analyzed cross-sectional data on social network size and cognitive functioning that were available for 804 participants aged 40-60 years. In addition, we examined 5- and 10-year follow-up measurements of cognitive functioning that were available for 604 and 255 participants, respectively. Cross-sectional analyses revealed a positive association between social network size and each of the three cognitive abilities. Baseline network size was positively related to 5-year changes in semantic memory, and to 10-year changes in semantic as well as episodic memory, but was unrelated to changes in visuospatial performance. A minor portion of the sample ( n  = 131) had 10-year follow-up data on network size. Cross-lagged panel correlations revealed that baseline network size was associated with follow-up measurement in cognitive functioning (episodic memory, semantic memory), whereas baseline cognitive performance was unrelated to future network size. Together, the results demonstrate a small but positive relation between network size and declarative memory abilities, in line with models proposing a cognitive reserve built up by factors such as the increased cognitive stimulation associated with a more extensive social network.

Background: Compared to high-flux dialysis membranes, novel medium cut-off (MCO) membranes show greater permeability for larger middle molecules., Methods: 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., Results: 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., Conclusions: 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., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.)

Understanding the genetic factors underlying brain structural connectivity is a major challenge in imaging genetics. Here, we present results from genome-wide association studies (GWASs) of whole-brain white matter (WM) fractional anisotropy (FA), an index of microstructural coherence measured using diffusion tensor imaging. Data from independent GWASs of 355 Swedish and 250 Norwegian healthy adults were integrated by meta-analysis to enhance power. Complementary GWASs on behavioral data reflecting processing speed, which is related to microstructural properties of WM pathways, were performed and integrated with WM FA results via multimodal analysis to identify shared genetic associations. One locus on chromosome 17 (rs145994492) showed genome-wide significant association with WM FA (meta P value = 1.87 × 10 -08 ). Suggestive associations (Meta P value <1 × 10 -06 ) were observed for 12 loci, including one containing ZFPM2 (lowest meta P value = 7.44 × 10 -08 ). This locus was also implicated in multimodal analysis of WM FA and processing speed (lowest Fisher P value = 8.56 × 10 -07 ). ZFPM2 is relevant in specification of corticothalamic neurons during brain development. Analysis of SNPs associated with processing speed revealed association with a locus that included SSPO (lowest meta P value = 4.37 × 10 -08 ), which has been linked to commissural axon growth. An intergenic SNP (rs183854424) 14 kb downstream of CSMD1, which is implicated in schizophrenia, showed suggestive evidence of association in the WM FA meta-analysis (meta P value = 1.43 × 10 -07 ) and the multimodal analysis (Fisher P value = 1 × 10 -07 ). These findings provide novel data on the genetics of WM pathways and processing speed, and highlight a role of ZFPM2 and CSMD1 in information processing in the brain.

Objective: Elevated cortisol levels with aging have been associated with atrophy of the hippocampus and prefrontal cortex (PFC), as well as with impaired cognitive functions in men. However, coexisting diseases have confounded many studies examining these relationships. Studies in women are lacking. Our objective was to test whether salivary cortisol levels were related to morphology of the hippocampus and the PFC, and to cognitive performance., Design: A cross-sectional study including 200 elderly (55-80 years old) men and women., Method: We used magnetic resonance imaging, tests of episodic-, semantic-, and working memory, visuospatial ability, and cortisol levels in four saliva samples collected during 1 day., Results: Area under the curve (AUC) for cortisol levels was negatively related to cortical surface area of the left anterior cingulate gyrus (caudal P<0.001; rostral P=0.006), right lateral orbitofrontal cortex (P=0.004), and right rostral middle frontal gyrus (P=0.003). In women, there was also a negative relationship with cortical surface area in the left rostral middle frontal gyrus (P=0.006). No relationship was found between cortisol levels and hippocampal volume., Conclusion: This study suggests that the structure of the medial PFC is related to cortisol levels in both elderly women and men., (© 2016 European Society of Endocrinology.)

The ɛ4 allele of the Apolipoprotein E gene is a genetic risk factor for late-onset dementia of the Alzheimers' type (DAT), which is characterized by loss of both episodic memory and olfactory functions. Little is known about the possible role of ɛ4 in the association between ongoing episodic memory decline and olfactory deficits in the general population, but such information is relevant in determining the relevance of olfaction as a marker of DAT risk. The present study was based on a large, population-based sample (n=1087, aged 45-90 years, of which 324 were ɛ4-carriers). Episodic memory change rates were established using data collected every 5 years for a 10-20 year interval leading up to an olfactory assessment using the Scandinavian Odor Identification Test at the last wave of data collection. Participants were classified according to whether or not their episodic memory ability declined more rapidly than the age-typical norm (by >1SD). Our main result is that only in ɛ4-carriers was episodic memory decline associated with odor identification impairment. In individuals without ɛ4, odor identification was unrelated to episodic memory decline status. Follow-up analyses indicated that this moderation by ɛ4 was due to the olfactory nature of the identification test, and that the effect was not caused by 63 individuals with dementia. Our results suggest that the ɛ4 determines the functional association between ongoing episodic memory decline and olfaction. These findings are consistent with the notion that ɛ4-carriers with DAT, compared to non-carriers, display a cortical atrophy pattern that is more focused on mediotemporal lobe regions supporting olfactory and episodic memory functions. Olfactory and memory assessments might provide complementary information on mediotemporal atrophy prior to clinical dementia onset, but the ɛ4 should be considered when using olfactory assessment as an early-stage indicator., (Copyright © 2016. Published by Elsevier Ltd.)

Identification of novel candidate genes for schizophrenia (SZ) and bipolar disorder (BP), two psychiatric disorders with large epidemiological impacts, is a key research area in neurosciences and psychiatric genetics. Previous evidence from genome-wide studies suggests an important role for genes involved in synaptic plasticity in the risk for SZ and BP. We used a convergent genomics approach, combining different lines of biological evidence, to identify genes involved in the cAMP/PKA/CREB functional pathway that could be novel candidates for BP and SZ: CREB1, CREM, GRIN2C, NPY2R, NF1, PPP3CB and PRKAR1A. These 7 genes were analyzed in a HapMap based association study comprising 48 common SNPs in 486 SZ, 351 BP patients and 514 control individuals recruited from an isolated population in Northern Sweden. Genetic analysis showed significant allelic associations of SNPs in PRKAR1A with SZ and of PPP3CB and PRKAR1A with BP. Our results highlight the feasibility and the importance of convergent genomic data analysis for the identification of candidate genes and our data provide support for the role of common inherited variants in synaptic genes and their involvement in the etiology of BP and SZ., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Exposure to ambient air pollution is suspected to cause cognitive effects, but a prospective cohort is needed to study exposure to air pollution at the home address and the incidence of dementia., Objectives: We aimed to assess the association between long-term exposure to traffic-related air pollution and dementia incidence in a major city in northern Sweden., Methods: Data on dementia incidence over a 15-year period were obtained from the longitudinal Betula study. Traffic air pollution exposure was assessed using a land-use regression model with a spatial resolution of 50 m × 50 m. Annual mean nitrogen oxide levels at the residential address of the participants at baseline (the start of follow-up) were used as markers for long-term exposure to air pollution., Results: Out of 1,806 participants at baseline, 191 were diagnosed with Alzheimer's disease during follow-up, and 111 were diagnosed with vascular dementia. Participants in the group with the highest exposure were more likely than those in the group with the lowest exposure to be diagnosed with dementia (Alzheimer's disease or vascular dementia), with a hazard ratio (HR) of 1.43 (95% CI: 0.998, 2.05 for the highest vs. the lowest quartile). The estimates were similar for Alzheimer's disease (HR 1.38) and vascular dementia (HR 1.47). The HR for dementia associated with the third quartile versus the lowest quartile was 1.48 (95% CI: 1.03, 2.11). A subanalysis that excluded a younger sample that had been retested after only 5 years of follow-up suggested stronger associations with exposure than were present in the full cohort (HR = 1.71; 95% CI: 1.08, 2.73 for the highest vs. the lowest quartile)., Conclusions: If the associations we observed are causal, then air pollution from traffic might be an important risk factor for vascular dementia and Alzheimer's disease.

Background/aims: Hemodialysis (HD) patients often show impaired response to erythropoiesis-stimulating agents (ESAs). Extended HD membrane permeability may potentially improve ESA response., Methods: Twenty-four prevalent HD patients were randomly assigned to 12 weeks use of high cut-off (HCO) membrane (in every second dialysis treatment) or continued treatment with high-flux membrane. We monitored changes in hemoglobin (Hb), ESA dose, and key biochemical markers., Results: The Hb level increased in the study group (from 11.6 ± 1.0 to 12.5 ± 1.5 g/dl; p = 0.038) but was stable in the control group. Variation over time in ESA dose and ESA resistance index did not differ between groups. HCO membrane usage for 12 weeks led to decreased hepcidin level, from 303 ± 189 to 157 ± 83 ng/ml (p = 0.024); serum albumin level decreased and stabilized 15 ± 6% below baseline., Conclusions: These results indicate that use of a more permeable dialysis membrane may improve ESA responsiveness in iron-replete HD patients. Extensive albumin removal may preclude long-term use of the HCO membrane., (© 2015 S. Karger AG, Basel.)

Introduction: The objective was to examine whether subjective memory impairment (SMI) predicts all-cause dementia or Alzheimer's disease (AD) in a population-based study with long-term follow-up (median = 10 years)., Methods: A total of 2043 initially dementia-free participants (≥ 60 years) made three memory ratings ("compared with others", "compared with five years ago", and "complaints from family/friends") at baseline. During follow-up, 372 participants developed dementia (208 with AD)., Results: Cox regression revealed that subjective memory impairment ratings predicted all-cause dementia in models adjusting for age and sex (hazard ratio or HR from 2.04 to 3.94), with even higher values for AD (HR from 2.29 to 5.74). The result persisted in models including other covariates, including baseline episodic memory performance, and in analyses restricted to participants with long time to dementia diagnosis (≥ 5 years)., Discussion: The findings underscore the usefulness of subjective memory assessment in combination with other factors in identifying individuals at risk for developing dementia., (Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Testing one's memory of previously studied information reduces the rate of forgetting, compared to restudy. However, little is known about how this direct testing effect applies to action phrases (e.g., "wash the car") - a learning material relevant to everyday memory. As action phrases consist of two different components, a verb (e.g., "wash") and a noun (e.g., "car"), testing can either be implemented as noun-cued recall of verbs or verb-cued recall of nouns, which may differently affect later memory performance. In the present study, we investigated the effect of testing for these two recall types, using verbally encoded action phrases as learning materials. Results showed that repeated study-test practice, compared to repeated study-restudy practice, decreased the forgetting rate across 1 week to a similar degree for both noun-cued and verb-cued recall types. However, noun-cued recall of verbs initiated more new subsequent learning during the first restudy, compared to verb-cued recall of nouns. The study provides evidence that testing has benefits on both subsequent restudy and long-term retention of action-relevant materials, but that these benefits are differently expressed with testing via noun-cued versus verb-cued recall., (© 2015 Scandinavian Psychological Associations and John Wiley & Sons Ltd.)

Robust statistical, genetic and functional evidence supports a role for DISC1 in the aetiology of major mental illness. Furthermore, many of its protein-binding partners show evidence for involvement in the pathophysiology of a range of neurodevelopmental and psychiatric disorders. Copy number variants (CNVs) are suspected to play an important causal role in these disorders. In this study, CNV analysis of DISC1 and its binding partners PAFAH1B1, NDE1, NDEL1, FEZ1, MAP1A, CIT and PDE4B in Scottish and Northern Swedish population-based samples was carried out using multiplex amplicon quantification. Here, we report the finding of rare CNVs in DISC1, NDE1 (together with adjacent genes within the 16p13.11 duplication), NDEL1 (including the overlapping MYH10 gene) and CIT . Our findings provide further evidence for involvement of DISC1 and its interaction partners in neuropsychiatric disorders and also for a role of structural variants in the aetiology of these devastating diseases.

We investigated the factorial structure of the Perceived Stress Questionnaire (PSQ-recent; Levenstein, Prantera, Varvo et al., 1993) in a large (N = 1516; 35-95 years) population-based Swedish sample (Nilsson, Adolfsson, Bäckman et al., 2004; Nilsson, Bäckman, Erngrund et al., 1997). Exploratory principal components analysis (PCA) was conducted on a first, randomly drawn subsample (n = 506). Next, the model based on the PCA was tested in a second sample (n = 505). Finally, a third sample (n = 505) was used to cross-validate the model. Five components were extracted in the PCA (eigenvalue > 1) and labeled "Demands," "Worries/Tension," "Lack of joy," "Conflict," and "Fatigue," respectively. Twenty-one out of the 30 original PSQ items were retained in a confirmatory factor analysis (CFA) model that included the five (first-order) factors and, additionally, a general (second-order) stress factor, not considered in prior models. The model showed reasonable goodness of fit [χ(2)(184) = 511.2, p < 0.001; CFI = 0.904; RMSEA = 0.059; and SRMR = 0.063]. Multigroup confirmatory factor analyses supported the validity of the established model. The results are discussed in relation to prior investigations of the factorial structure of the PSQ., (© 2015 Scandinavian Psychological Associations and John Wiley & Sons Ltd.)

Introduction: The Activity-Regulated Cytoskeleton-associated (ARC) gene encodes a protein that is critical for the consolidation of synaptic plasticity and long-term memory formation. Given ARC's key role in synaptic plasticity, we hypothesized that genetic variations in ARC may contribute to interindividual variability in human cognitive abilities or to attention-deficit hyperactivity disorder (ADHD) susceptibility, where cognitive impairment often accompanies the disorder., Methods: We tested whether ARC variants are associated with six measures of cognitive functioning in 670 healthy subjects in the Norwegian Cognitive NeuroGenetics (NCNG) by extracting data from its Genome-Wide Association Study (GWAS). In addition, the Swedish Betula sample of 1800 healthy subjects who underwent similar cognitive testing was also tested for association with 19 tag SNPs., Results: No ARC variants show association at the study-wide level, but several markers show a trend toward association with human cognitive functions. We also tested for association between ARC SNPs and ADHD in a Norwegian sample of cases and controls, but found no significant associations., Conclusion: This study suggests that common genetic variants located in ARC do not account for variance in human cognitive abilities, though small effects cannot be ruled out.

Objectives: To examine the association between self-reported memory failures and incident dementia in individuals aged 60 and older., Design: Longitudinal, community based., Setting: Betula Prospective Cohort Study, a population-based study in Umeå, Sweden., Participants: Individuals with a mean age of 71.5 ± 8.8 (range 60-90) (N = 1,547)., Measurements: Participants rated the frequency of everyday memory failures using the 16-item Prospective and Retrospective Memory Questionnaire (PRMQ) and underwent objective memory testing at baseline. Participant self-reports of complaints of poor memory by family and friends were evaluated. Dementia status was followed-up for 10 to 12 years., Results: Over the study period, 225 participants developed dementia (132 with Alzheimer's disease (AD)). In Cox proportional hazard regression models adjusted for demographic factors, PRMQz-scores predicted incident dementia (hazard ratio (HR) = 1.21 for all-cause dementia; HR = 1.25 for AD, Ps < .01). The significant associations remained when depressive symptoms and objective memory performance were adjusted for, when low performers on objective memory (≥1 standard deviations below the age group mean) were excluded, and in analyses with delayed entry (survival time ≥ 5 years). Similar patterns were observed for the prospective and retrospective subscales, although including how often participants self-reported that others complained about their poor memory eliminated the association between PRMQ scores and dementia and itself emerged as a significant predictor., Conclusion: Self-reported memory failure predicted future dementia or AD independent of objective memory performance. Subjective reports of complaints by family and friends appear to be an even more-important indicator of preclinical impairments, and physicians should not ignore them, even in the absence of objective memory deficits., (© 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.)

Purpose: Cognitive decline has been suggested as an early marker for later onset of Alzheimer's disease. We therefore explored the relationship between decline in episodic memory and β-amyloid using positron emission tomography (PET) and [(11)C]AZD2184, a radioligand with potential to detect low levels of amyloid deposits., Methods: Healthy elderly subjects with declining (n = 10) or stable (n = 10) episodic memory over 15 years were recruited from the population-based Betula study and examined with PET. Brain radioactivity was measured after intravenous administration of [(11)C]AZD2184. The binding potential BP ND was calculated using linear graphical analysis with the cerebellum as reference region., Results: The binding of [(11)C]AZD2184 in total grey matter was generally low in the declining group, whereas some binding could be observed in the stable group. Mean BP ND was significantly higher in the stable group compared to the declining group (p = 0.019). An observation was that the three subjects with the highest BP ND were ApoE ε4 allele carriers., Conclusions: We conclude that cognitive decline in the general population does not seem to stand by itself as an early predictor for amyloid deposits.

Background: The objective was to examine whether aspects of social relationships in old age are associated with all-cause dementia and Alzheimer's disease (AD)., Methods: 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., Results: 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., Conclusions: 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.

Introduction: The serotonin 5-HT1B receptor subtype is involved in the modulation of serotonin release and is a target of interest for neuroreceptor imaging. Previous studies have shown that the serotonin system is affected in Parkinson's disease (PD). Cognitive function, frequently impaired in PD, has been linked to the serotonin system. The aim of this study was to examine whether 5-HT1B receptor availability in the brain of healthy subjects and PD patients is associated with measures of cognitive function., Methods: Twelve control subjects and ten PD patients with normal mini-mental state examination scores were included in this study. Cognitive function was evaluated by assessment of semantic, episodic, and working memory, as well as fluency and visual attention. Creative ability, a measure of divergent thinking, was examined with the alternative uses of objects task. PET measurements were performed with the 5-HT1B receptor-radioligand [(11) C]AZ10419369 using the HRRT system., Results: PD patients showed statistically significant lower measures of semantic and episodic memory, as well as creative ability, compared with control subjects. Statistically significant positive correlations were found in control subjects between creative ability and average 5-HT1B receptor availability in grey matter, and in PD patients between scores of Beck Depression Inventory-II and creative ability., Conclusion: Though creativity has been conventionally linked to dopamine function, our findings in control subjects suggest a link between 5-HT1B receptor availability and creative ability. In PD patients, creative ability was significantly associated with depressive symptoms but not with 5-HT1B receptor availability. This finding deserves further investigation in future studies., (© 2015 Wiley Periodicals, Inc.)

Background: Previous studies have suggested a link between herpes simplex virus (HSV) type 1 and the development of Alzheimer's disease (AD)., Methods: The present analysis included 3432 persons (53.9% women, mean age at inclusion 62.7 ± 14.4 years) with a mean follow-up time of 11.3 years. The number of incident AD cases was 245. Serum samples were analyzed for anti-HSV antibodies (immunoglobulin (Ig)G and IgM) by enzyme-linked immunosorbent assays., Results: The presence of anti-HSV IgG antibodies was not associated with an increased risk for AD, controlled for age and sex (hazard ratio, HR, 0.993, P = .979). However, the presence of anti-HSV IgM at baseline was associated with an increased risk of developing AD (HR 1.959, P = .012)., Conclusion: Positivity for anti-HSV IgM, a sign of reactivated infection, was found to almost double the risk for AD, whereas the presence of anti-HSV IgG antibodies did not affect the risk., (Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background/aims: Early dementia diagnosis is a considerable challenge. The present study examined the predictive value of cognitive performance for a future clinical diagnosis of late-onset Alzheimer's disease or vascular dementia in a random population sample., Methods: Cognitive performance was retrospectively compared between three groups of participants from the Betula longitudinal cohort. Group 1 developed dementia 11-22 years after baseline testing (n = 111) and group 2 after 1-10 years (n = 280); group 3 showed no deterioration towards dementia during the study period (n = 2,855). Multinomial logistic regression analysis was used to investigate the predictive value of tests reflecting episodic memory performance, semantic memory performance, visuospatial ability, and prospective memory performance., Results: Age- and education-corrected performance on two free recall episodic memory tests significantly predicted dementia 10 years prior to clinical diagnosis. Free recall performance also predicted dementia 11-22 years prior to diagnosis when controlling for education, but not when age was added to the model., Conclusion: The present results support the suggestion that two free recall-based tests of episodic memory function may be useful for detecting individuals at risk of developing dementia 10 years prior to clinical diagnosis.

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

Background: Elevated concentrations of plasma glucose appear to play a role in memory impairment, and it has been suggested that insulin might also have a negative effect on cognitive function. Our aim was to study whether glucose, insulin or insulin resistance are associated with episodic or semantic memory in a non-diabetic and non-demented population., Methods: We linked and matched two population-based data sets identifying 291 participants (127 men and 164 women, mean age of 50.7 ± 8.0 years). Episodic and semantic memory functions were tested, and fasting plasma insulin, fasting plasma glucose, and 2-hour glucose were analysed along with other potential influencing factors on memory function. Since men and women display different results on memory functions they were analysed separately. Insulin resistance was calculated using the HOMA-IR method., Results: A higher fasting plasma glucose concentration was associated with lower episodic memory in women (r = -0.08, 95% CI -0.14; -0.01), but not in men. Plasma insulin levels and insulin resistance were not associated with episodic or semantic memory in women or in men after adjustments for age, fasting glucose, 2-hour glucose, BMI, education, smoking, cardiovascular disease, hypertension, cholesterol, and physical activity., Conclusions: This indicates that fasting glucose but not insulin, might have impact on episodic memory in middle-aged women.