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Background: Higher anxiety levels in older adults are associated with worse executive functioning and an increased risk for dementia. In this study individual anxiety disorders and clinically relevant generalized anxiety symptoms are studied in relation to multiple cognitive domains.Method: This cross-sectional study includes 7344 community-dwelling participants of The Maastricht Study aged 40-75 years and oversampling of type 2 diabetes. Panic disorder with and without agoraphobia, agoraphobia and lifetime panic disorder were measured with the Mini International Neuropsychiatric Interview. Generalized anxiety symptoms were measured with the Generalized Anxiety Disorder 7-item scale (GAD-7). Multiple cognitive domains (executive functioning, memory and processing speed) and cognitive impairment were assessed. Multivariable linear and logistic regression analyses were used with adjustment for potential confounders. Interaction analyses were performed to test the moderation of age, sex and type 2 diabetes (due to oversampling).Results: Agoraphobia was associated with worse scores on all cognitive domains (range B = -0.12 to -0.10; range 95%CI = -0.20 to -0.04) and with higher odds of cognitive impairment (OR = 1.51, 95%CI = 1.18-1.93). High scores on the GAD-7 were associated with worse scores on processing speed (B = -0.11, 95%CI = -0.20 to -0.03) and higher odds of cognitive impairment (OR = 1.42, 95%CI = 1.02-1.97). Panic disorder was significantly associated with worse scores on memory tasks (B = -0.25, 95%CI = -0.48 to -0.02). Associations were stronger in the younger participants and for agoraphobia and GAD-7 scores also in those with type 2 diabetes.Conclusion: Multiple anxiety disorders and generalized anxiety symptoms were associated with worse cognitive functioning on several cognitive domains. [ABSTRACT FROM AUTHOR]

• Noradrenaline turnover and cortical thickness are related at high biomarker levels. • This noradrenaline turnover and thickness relation occurs at subthreshold amyloid. • Locus coeruleus function may be an indicator of Alzheimer-related brain morphology. Advanced Alzheimer's disease (AD) is characterized by higher noradrenaline metabolite levels that may be associated with AD pathology. The locus coeruleus (LC) is the main site for cerebral noradrenaline synthesis and LC volume loss occurs as early as Braak stage 1. This study investigates the association between noradrenergic turnover and brain morphology, and the modifying effect of AD pathology. The study sample included 77 memory clinic patients (37 cognitively unimpaired and 40 cognitively impaired (mild cognitive impairment or AD dementia)). Cortical thickness and volumetric analyses were performed using FreeSurfer. Cerebrospinal fluid was analyzed for noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), Aβ42 and phosphorylated tau. Higher MHPG was associated with lower cortical thickness and hippocampal volume at lower, but subthreshold, levels of Aβ42 and at higher p-tau levels. These associations remained significant after adding APOE-E4 or cognitive status as covariates. Our results suggest that greater MHPG together with worse AD pathology contributes to neurodegeneration, possibly before significant amyloidosis. The noradrenergic system may play an important role in early detection of AD-related processes. [ABSTRACT FROM AUTHOR]

Background: Type D personality - the combination of negative affectivity (NA) and social inhibition (SI) - has been associated with depression but little is known about underlying mechanisms. We examined whether (1) Type D is a vulnerability factor for depression in general, (2) Type D is associated with inflammation or endothelial dysfunction, and (3) these biomarkers alter the possible association between Type D and depression.Methods: In the Maastricht Study, 712 subjects underwent assessment of NA, SI and Type D personality (DS14), depressive disorder (Mini-International Neuropsychiatric Interview) and depressive symptoms (Patient Health Questionnaire-9). Plasma biomarkers of inflammation (hsCRP, SAA, sICAM-1, IL-6, IL-8, TNF-α) and endothelial dysfunction (sVCAM-1, sICAM-1, E-selectin, vWF) were measured with sandwich immunoassays or ELISA and combined into standardized sumscores.Results: Regarding personality, 49% of the study population was low in NA and SI, 22% had SI only, 12% NA only and 17% had Type D. Depressive disorder and depressive symptoms were significantly more prevalent in Type D versus the other three personality subgroups. Multivariable regression analyses showed that Type D was associated with inflammation (β=0.228, p=0.014) and endothelial dysfunction (β=0.216, p=0.022). After adjustment for these biomarkers, Type D remained independently associated with increased vulnerability to depressive disorder (OR=13.20, p<0.001) and depressive symptoms (β=3.87, p<0.001).Limitations: The cross-sectional design restrained us to draw any conclusions on causality. The relatively low prevalence of depressive disorder restrained us to adjust for more potential confounders.Conclusions: Type D personality may be a vulnerability factor for depression, irrespective of levels of inflammation or endothelial dysfunction. Future research should examine possible underlying mechanisms. [ABSTRACT FROM AUTHOR]

Highlights: [•] An early dementia diagnosis offers caregivers the opportunity to advance the process of adaptation to the caregiver role. [•] Caregivers that are able to adapt to the changes that characterize dementia, feel more competent to care and experience less psychological problems. [•] Multicomponent caregiver interventions in the mild to moderate dementia stages are effective to improve caregiver well-being and delay institutionalization. [•] Offering caregiver interventions in the predementia stage asks for different approaches with different tasks to cope with. [ABSTRACT FROM AUTHOR]

Abstract: In Parkinson''s disease (PD) reduced dopaminergic activity in the mesocorticolimbic pathway is implied in the pathophysiology of several non-motor symptoms related to mood, motivation and cognition. Insight in the pathophysiology of these syndromes may pave the way for more rational treatments. In a double-blind, randomized, placebo controlled, crossover design with three arms, we studied the effects of a direct dopaminergic challenge with the dopamine 2 receptor agonist pramipexole, an indirect challenge with the dopamine reuptake inhibitor methylphenidate, and placebo on measures of mood, motivation and cognition in 23 agonist-naïve PD patients and 23 healthy controls. Acute challenge with pramipexole had a negative effect on mood and fatigue in both patients and controls. In addition, challenge with pramipexole led to increased anger, fatigue, vigor and tension in healthy control subjects, but not in PD patients. Challenge with methylphenidate had a positive effect on anhedonia and vigor in PD patients. Due to its side effects after a single administration, pramipexole is probably less suitable for acute challenge studies. The acute effects of a methylphenidate challenge on anhedonia and vigor in PD patients make this drug an interesting choice for further studies of the treatment of mood and motivational disorders in this population. [Copyright &y& Elsevier]

Objectives: Memory clinics (MCs) are multidisciplinary teams involved with early diagnosis and treatment of people with dementia. The main aim of this study was to gain more insight into the development of MCs in the Netherlands since 1998. Methods: In 1998, 2004 and 2009, an MC survey with questions about patient groups, organisation and working procedures of the MC were sent to all MCs in the Netherlands. Results: The number of MCs increased from 12 in 1998, to 43 in 2004 and to 63 in 2009. In 2009, MCs were better embedded with other regional care and were delivering services for dementia with less emphasis on university-based research. While dementia was still the most common syndromal diagnosis, the proportion of subjects diagnosed with milder memory problems increased to 39%. Diagnostic tools, blood assessments and brain imaging were used in nearly all the facilities. There was an increase both in the use of extensive neuropsychological assessments and in the use of cerebrospinal fluid diagnostics. Conclusion: MCs in the Netherlands have outgrown the primarily university-based setting, have focussed less on scientific research, and have taken a place in the regular care of people with cognitive problems and people in early phases of dementia. [ABSTRACT FROM AUTHOR]

Abstract: Background: Parkinson''s disease (PD) is a neuropsychiatric disease, which is not only characterized by motor symptoms, but also by cognitive and psychiatric symptoms. It is hypothesized that some of the non-motor symptoms are related to the serotonergic deficiency that is present in PD. Aim: To study the influence of serotonin on cognition, memory and motor performance in PD. Methods: In a double blind, randomized, placebo-controlled, cross-over design, the effect of acute tryptophan depletion (ATD) on the Visual Verbal Learning Task (VVLT), the Concept Shifting Task (CST), Simple Reaction Time Task (SRT), Finger Precuing Task (FPT) and the motor section of the Unified Parkinson''s Disease Rating Scale (UPDRS, Section 3) was investigated in 15 PD patients in early stages of their disease and 15 healthy volunteers, matched for age, sex and educational status. Results: With the exception of the absence of a differential effect for PD patients with the long interval of the SRT, ATD produced similar effects in PD patients and control subjects on all tasks. These included impairment of delayed recall and delayed recognition on the VVLT, and improved SRT and FPT for ‘short intervals’. The UPDRS in patients remained unaffected after ATD. Conclusion: Serotonin does not appear to play a disease-specific role in cognition and reaction time in early stage PD patients, nor does acute reduction of cerebral serotonin levels affect motor symptoms in a clinically relevant way. [Copyright &y& Elsevier]

Abstract: Behavioral and psychological symptoms of dementia (BPSD), constitute a major clinical component of Alzheimer’s disease (AD). There is a growing interest in BPSD as they are responsible for a large share of the suffering of patients and caregivers, and they strongly determine the patient’s lifestyle and management. Better detection and understanding of these symptoms is essential to provide appropriate management. This article is a consensus produced by the behavioral group of the European Alzheimer’s Disease Consortium (EADC). The aim of this article is to present clinical description and biological correlates of the major behavioral and psychological symptomatology in AD. BPSD is not a unitary concept. Instead, it should be divided into several symptoms or more likely: groups of symptoms, each possibly reflecting a different prevalence, course over time, biological correlate and psychosocial determinants. There is some clinical evidence for clusters within groups of BPSD. Biological studies indicate that patients with AD and BPSD are associated with variations in the pathological features (atrophy, brain perfusion/metabolism, histopathology) when compared to people with AD without BPSD. An individually tailored approach taking all these aspects into account is warranted as it may offer more, and better, pharmacological and non-pharmacological treatment opportunities. [Copyright &y& Elsevier]

The article discusses the use of memory clinics or memory services in western countries to care for older people suffering the early stages of dementia. Though such services reportedly were first used for research purposes, they have become central to dementia diagnosis, education, and treatment. Research is discussed that has shown the benefits of such care to the quality of life of patients and caregivers.

Background: It is uncertain whether self- and proxy-reported cognitive decline in older adults reflect an actual objective cognitive dysfunction in the clinical sense, and if these are predictive for developing dementia.Objective: The aim of the present study is to investigate the cross-sectional and longitudinal relation between subjective cognitive decline and objective cognitive performance, depressive symptoms, and to determine the predictive value for development of dementia.Methods: We included 405 patients without dementia at first visit from the Maastricht memory clinic participating in a longitudinal cohort study. Subjective cognitive decline was measured using a self- and proxy-report questionnaire. All patients underwent a standardized neuropsychological assessment. Follow-up assessments were performed yearly for three consecutive years, and once after five years.Results: Subjective cognitive decline was associated with lower cognitive performance and more depressive symptoms. When comparing self- (n = 342, 84%) and proxy-reported decline (n = 110, 27%), it was shown that proxy reports were associated with a more widespread pattern of lower cognitive performance. In participants without cognitive impairment proxy-reported decline was not associated with depressive symptoms. In contrast, self-reported decline was associated with a stable course of depressive symptoms at follow-up. Proxy-reported cognitive decline (HR = 1.76, 95% CI = 1.12- 2.78), and mutual complaints (HR = 1.73, CI:1.09- 2.76) predicted incident dementia while self-reported decline did not reach statistical significance (HR = 1.26, 95% CI = 0.65- 2.43).Conclusion: Proxy-reported cognitive decline was consistently associated with lower cognitive performance and conversion to dementia over 5 years. Self-reported cognitive decline in patients without cognitive impairment might indicate underlying depressive symptoms and thus deserve clinical attention as well. [ABSTRACT FROM AUTHOR]

Measures of amyloid-β (Aβ) and phosphorylated tau (p-tau) concentrations in cerebrospinal fluid are extensively used for diagnostic and research purposes in Alzheimer's disease (AD) as correlates of cortical thinning and cognitive outcomes. The present study investigated the relationship of Aβ and p-tau with hippocampal subfield volumes Cornu Ammonis (CA) 1-4, dentate gyrus (DG), and subiculum. Subfields were segmented from T1-weighted images from the ADNI-population using FreeSurfer v6. Linear and polynomial regression models revealed distinct associations of Aβ and p-tau with subfield volumes. Aβ had a quadratic relationship with all hippocampal subfield volumes and the inflection point was higher than the validated cut-off for Aβ. For p-tau the relationships were linear, except for CA3, in which it was quadratic. For the CA1 and CA3, these quadratic relationships with Aβ were only observed when p-tau was low. Amyloid and p-tau contributed equally to the explained variance in CA4 and DG volume. Subicular volume was best explained by Aβ alone. These biomarker relationships with hippocampal subfield volumes seem to mirror the hippocampal-specific topography of Aβ and tau reported in neuropathological staging models. In addition, using continuous values of Aβ reveals positive patterns with imaging markers for individuals around the positivity threshold that would be masked when using dichotomized biomarker groups, which can be important for early detection and accurate inclusion of potential participants at risk for AD in clinical trials. [ABSTRACT FROM AUTHOR]

Objective: Post-stroke depression (PSD) and post-stroke apathy (PSA) are both associated with adverse outcome after stroke. This study aimed to examine whether personality traits predict the course of PSD and PSA.Methods: In this prospective cohort study, 240 stroke patients completed the NEO Five Factor Inventory, Montgomery-Åsberg Depression Rating Scale, and Apathy Evaluation Scale at 3 months post-stroke. Neuropsychiatric assessment was repeated at 6- and 12-month follow-up after initial testing.Results: Linear mixed models showed that high neuroticism scores were associated with higher depression levels at baseline, and this association remained stable at follow-up. High extraversion scores and high conscientiousness scores were associated with lower apathy levels at baseline. For neuroticism, a significant interaction with time was found, with higher neuroticism scores at baseline being associated with an increase in apathy scores from 6-month to 12-month follow-up. Prospective analyses showed that high extraversion predicted low apathy levels at 6-month and 12-month follow-up independent of its relations with baseline depression and apathy. High neuroticism predicted high apathy levels at 12-month follow-up, whereas high agreeableness and high openness predicted high apathy levels and low apathy levels, respectively, at 6-month follow-up. None of the personality traits predicted depression scores at follow-up.Conclusion: Personality traits are associated with the development and sustainability of PSD and PSA. The traits associated with PSD and PSA were different, providing support for the independence of these constructs. The findings highlight the importance to take personality traits into account as a potential vulnerability factor for PSD and PSA. [ABSTRACT FROM AUTHOR]

• Plasma levels of all kynurenines were positively correlated with those in CSF. • Correlations between plasma and CSF were strongest for QA. • QA showed a tendency for positive associations with CSF Aβ 1-42. • KYN, KA, and KTR in CSF were all positively associated with CSF Aβ 1-42. • KYN, both in plasma and CSF, was negatively associated with CSF p-tau. Altered levels of kynurenines in blood and cerebrospinal fluid (CSF) have been reported in Alzheimer's disease (AD). However, it is still largely unknown whether peripheral kynurenine concentrations resemble those found in CSF and how they relate to AD pathology. We therefore studied correlations between kynurenines in plasma and CSF and their associations with CSF amyloid-beta (Aβ 1-42) and tau levels in patients from the memory clinic spanning the whole cognitive spectrum. The Biobank Alzheimer Center Limburg study is a prospective cohort study of consecutive patients referred to the memory clinic of the Alzheimer Center Limburg. Plasma and CSF concentrations of tryptophan (TRP), eight kynurenines and neopterin from 138 patients were determined by means of LC-MS/MS. Additionally, CSF Aβ 1-42 , total-tau (t-tau) and phosphorylated tau (p-tau) concentrations were determined using commercially available single-parameter ELISA methods. Partial correlations were used to analyze cross-sectional associations between kynurenines in plasma and CSF and their relation to AD related CSF-biomarkers adjusted for age, sex, educational level, and kidney function. Moderate to strong correlations were observed between plasma and CSF levels for quinolinic acid (QA; r = 0.63), TRP (r = 0.47), anthranilic acid (r = 0.59), picolinic acid (r = 0.55), and the kynurenine (KYN)/TRP ratio (KTR; r = 0.55; all p < 0.0001), while other kynurenines correlated only weakly with their corresponding CSF values. No correlations were found between plasma and CSF levels of KA/QA. Several kynurenines were also weakly correlated with Aβ 1-42 , t-tau or p-tau. Plasma levels of KA/QA were negatively correlated with Aβ 1-42 (r = -0.21, p < 0.05). Plasma levels of TRP were negatively correlated with t-tau (r = -0.19) and levels of KYN with p-tau (r = -0.18; both p < 0.05). CSF levels of KYN (r = 0.20, p < 0.05), KA (r = 0.23, p < 0.01), and KTR (r = 0.18, p < 0.05) were positively correlated with Aβ 1-42. Finally, TRP and KYN were negatively (r = -0.22 and r = -0.18, respectively), and neopterin positively (r = 0.19) correlated with p-tau (all p < 0.05). Plasma concentrations of TRP, KP metabolites, KTR, and neopterin all significantly correlated positively with their corresponding CSF concentrations, but many correlations were weak. Additionally, our results suggest a relation between higher kynurenine levels and lower AD pathology load. These results need verification in future studies and require more research into (shared) underlying mechanisms. [ABSTRACT FROM AUTHOR]

Background: The progression of dementia in people with young-onset dementia (YOD) is relatively unknown.Objective: To investigate the progression of dementia and cognitive decline in the three most common subtypes in YOD and to explore which factors are associated with this course.Methods: The course of dementia was examined in 198 people with YOD. The primary outcomes were cognitive function, as assessed by the Mini-Mental State Examination (MMSE) and dementia severity, as assessed by the Global Deterioration Scale (GDS). Mixed-model analyses were used to explore factors associated with the course of dementia of the diagnostic sub-types.Results: The mean overall two-year progression of dementia severity was 0.9 GDS points, this was a statistically significant change (p = 0.012) and was not significant different for the three dementia subtypes. The mean overall two-year decline in cognitive function was 1.6 points on the MMSE. The differences in cognitive decline were statistically significant (p = 0.046) among the three diagnosis groups, AD participants showed the greatest decline, of 2.3 points. In addition to lower education (p = 0.010), higher scores on the Neuropsychiatric Inventory (NPI) sub-syndromes psychosis (p < 0.001) and hyperactivity (p = 0.002) were associated with higher rates of cognitive decline. In contrast, higher scores on the NPI affect cluster were associated with lower levels of cognitive decline (p < 0.001).Conclusion: Different YOD subtypes show different rates of decline in cognitive functioning, and this decline seems less progressive compared to those observed in studies in late-onset AD. Further research is needed to evaluate whether managing neuropsychiatric symptoms can positively influence the decline of cognitive function. [ABSTRACT FROM AUTHOR]

Background: Individuals with depression often show an adverse cardiometabolic risk profile and might represent a distinct depression subtype. The aim of this study was to investigate whether a cardiometabolic depression subtype could be identified and to investigate its association with demographics and clinical characteristics (severity, symptomatology, anti-depressant use, persistence and cognitive functioning).Methods: We used data from The Maastricht Study, a population-based cohort in the southern part of The Netherlands. A total of 248 participants with major depressive disorder were included (mean [SD] age, 58.8 ± 8.5 years; 121 [48.8 %] were men). Major depressive disorder was assessed at baseline by the Mini-International Neuropsychiatric Interview. Cardiometabolic risk factors were defined as indicators of the metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. We measured severity and persistence of depressive symptoms by use of the 9-item Patient Health Questionnaire.Results: Latent class analysis resulted in two subtypes, one with cardiometabolic depression (n = 145) and another with non-cardiometabolic depression (n = 103). The cardiometabolic depression subtype was characterized by being male, low education, more severe depressive symptoms, less symptoms of depressed mood and more symptoms of loss of energy, more use of antidepressant medication and lower cognitive functioning.Limitations: No conclusions can be made about causality.Conclusions: Latent class analysis suggested a distinct cardiometabolic depression subtype. Participants with cardiometabolic depression differed from participants with non-cardiometabolic depression in terms of demographics and clinical characteristics. The existence of a cardiometabolic depression subtype may indicate the need for prevention and treatment targeting cardiometabolic risk management. [ABSTRACT FROM AUTHOR]

Background: The association between health-related quality of life (HRQoL) and care costs in people at risk for cognitive decline is not well understood. Studying this association could reveal the potential benefits of increasing HRQoL and reducing care costs by improving cognition.Objective: In this exploratory data analysis we investigated the association between cognition, HRQoL utilities and costs in a well-functioning population at risk for cognitive decline.Methods: An exploratory data analysis was conducted using longitudinal 2-year data from the FINGER study (n = 1,120). A change score analysis was applied using HRQoL utilities and total medical care costs as outcome. HRQoL utilities were derived from the Short Form Health Survey-36 (SF-36). Total care costs comprised visits to a general practitioner, medical specialist, nurse, and days at hospital. Analyses were adjusted for activities of daily living (ADL) and depressive symptoms.Results: Although univariable analysis showed an association between cognition and HRQoL utilities, multivariable analysis showed no association between cognition, HRQoL utilities and total care costs. A one-unit increase in ADL limitations was associated with a -0.006 (p < 0.001) decrease in HRQoL utilities and a one-unit increase in depressive symptoms was associated with a -0.004 (p < 0.001) decrease in HRQoL utilities.Conclusion: The level of cognition in people at-risk for cognitive decline does not seem to be associated with HRQoL utilities. Future research should examine the level at which cognitive decline starts to affect HRQoL and care costs. Ideally, this would be done by means of cross-validation in populations with various stages of cognitive functioning and decline. [ABSTRACT FROM AUTHOR]

Objectives With the lack of a cure for Alzheimer disease (AD), the identification of comorbidity is important to reduce the possibility of excess disability. Although comorbidity in patients with late-onset AD (LO-AD) is common, for people with young-onset AD (YO-AD), it is unclear how often comorbidity occurs. Furthermore, it is uncertain whether comorbidity in patients with YO-AD differs from that in patients with LO-AD. The aim of this study was to explore the prevalence, types of morbidity, and morbidity profiles in patients with YO-AD compared with those of patients with LO-AD. Design Explorative cohort study from 2 separate Dutch cohorts (Needs in Young-onset Dementia [NeedYD] and the Clinical Course of Cognition and Comorbidity–Dementia Study [4C-Dementia study]). Setting Participants were recruited in 2007 and 2008 from (1) the memory clinics of 3 Dutch Alzheimer centers, (2) the memory clinics of general hospitals, (3) mental health services in the southern part of the Netherlands, and (4) young-onset dementia specialized day care facilities. A comparison group of community-dwelling, elderly patients with AD was selected from the 4C-Dementia study. Patients in this study were recruited in 2010 and 2011 from the aforementioned Alzheimer centers. Measurements The prevalence rates of comorbidity were compared between 177 patients with YO-AD and 155 patients with LO-AD. Comorbidity was classified using the International Classification of Diseases, 10th Revision (ICD-10). The total amount of comorbidity was established by counting the number of existing diseases (ICD categories or chapters) and comorbidity was also dichotomized as present or absent. Furthermore, a hierarchical cluster analysis was performed to study clusters of comorbidity. Results Compared with LO-AD, patients with YO-AD showed less ( P < .001) overall comorbidity (58.2% vs 86.5%) and had lower prevalence rates of diabetes, obesity, and circulatory diseases; however, the prevalence rates of diseases of the nervous system in YO-AD (6.2%) were higher compared with those of patients with LO-AD (4.5%). The cluster analysis revealed a distinctive group of patients with YO-AD with either no comorbidity or with a disease of the nervous system. Endocrine, nutritional, and metabolic diseases and diseases of the circulatory system were present in 34% of the patients with YO-AD. Conclusion Comorbidity is less common in YO-AD than in LO-AD. However, general practitioners should be aware that approximately one-third of the patients with YO-AD suffer from or have endocrine, nutritional, and metabolic diseases and/or diseases of the circulatory system. Treatment should therefore not only focus on dementia but also on comorbidity. This attention may slow the functional decline in AD. These exploratory analyses suggested a higher prevalence of nervous system diseases in YO-AD compared with LO-AD. However, the finding did not reach statistical significance and in combination with the exploratory nature of the analyses justifies further investigation. If verified, this finding may help to decrease the time to diagnosis of AD and, subsequently, support in young patients with a neurological disease. Further investigation is needed to gain more insight into the association between comorbidity and AD in younger people. [ABSTRACT FROM AUTHOR]

The brain-derived neurotropic growth factor (BDNF) gene has been linked to dementia, inflammation, and Apolipoprotein E (APOE) ɛ4 status. We used cerebrospinal fluid (CSF) amyloid-β (Aβ)42 and phosphorylated tau (p-tau) to investigate associations with BDNF polymorphisms and modifications by APOE ɛ4 or inflammation in a memory clinic population (n = 114; subjective cognitive decline, mild cognitive impairment, Alzheimer's disease). We found distinct pathways to Alzheimer's disease pathology: Val-Met displayed lower CSF-Aβ42 in APOE ɛ4+ carriers, independent of p-tau, while Val-Val displayed greater p-tau at higher IL-6 and sub-threshold Aβ42. This may contribute to resolving some inconsistencies in the BDNF literature and provide possible inroads to specific Aβ and tau interventions depending on BDNF polymorphism. [ABSTRACT FROM AUTHOR]

Background: The relation between vascular risk factors (VRFs) and Alzheimer's disease (AD) is important due to possible pathophysiological association.Objective: To assess the prevalence of VRFs in biomarker-based AT(N) groups and the associations between VRFs, AD cerebrospinal fluid (CSF) biomarkers, brain magnetic resonance imaging (MRI), and cognition in clinical context.Methods: We included patients from two memory clinics in University Hospital Aachen (Germany) and Maastricht University Medical Centre (The Netherlands). Subjects were older than 45 years and had available data on demographics, VRFs, CSF AD biomarkers, and MRI. We categorized individuals in normal AD biomarkers, non-AD change, and AD-continuum groups based on amyloid (A), tau (T), and neurodegeneration (N) status in CSF and MRI. Regression models were corrected for age, sex, and site.Results: We included 838 participants (mean age 68.7, 53.2% male, mean MMSE 24.9). The most common VRFs were smoking (60.9%), hypertension (54.6%), and dyslipidemia (37.8%). Alcohol abuse and smoking were most frequent in the non-AD-change group, and coronary heart disease and carotid artery stenosis in the AD continuum group. Higher rates of depression were found in the normal AD biomarkers group. Parietal atrophy and cortical microbleeds were specific for the AD continuum group. Carotid artery stenosis was associated with pathological Aβ42 and T-tau values, and diabetes and alcohol abuse were associated with worse medial temporal atrophy and atrial fibrillation, with worse cognition.Conclusion: VRFs are common in memory clinic patients, showing differences across the AT(N) biomarker groups. This is important for prevention and individualized treatment of dementia. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes is associated with increased risks of cognitive dysfunction and brain abnormalities. The extent to which risk factor modification can mitigate these risks is unclear. We investigated the associations between incident dementia, cognitive performance, and brain abnormalities among individuals with type 2 diabetes, according to the number of risk factors on target, compared with control subjects without diabetes.Research Design and Methods: Prospective data were from UK Biobank of 87,856 individuals (n = 10,663 diabetes, n = 77,193 control subjects; baseline 2006-2010), with dementia follow-up until February 2018. Individuals with diabetes were categorized according to the number of seven selected risk factors within the guideline-recommended target range (nonsmoking; guideline-recommended levels of glycated hemoglobin, blood pressure, BMI, albuminuria, physical activity, and diet). Outcomes were incident dementia, domain-specific cognitive performance, white matter hyperintensities, and total brain volume.Results: After a mean follow-up of 9.0 years, 147 individuals (1.4%) with diabetes and 412 control subjects (0.5%) had incident dementia. Among individuals with diabetes, excess dementia risk decreased stepwise for a higher number of risk factors on target. Compared with control subjects (incidence rate per 1,000 person-years 0.62 [95% CI 0.56; 0.68]), individuals with diabetes who had five to seven risk factors on target had no significant excess dementia risk (absolute rate difference per 1,000 person-years 0.20 [-0.11; 0.52]; hazard ratio 1.32 [0.89; 1.95]). Similarly, differences in processing speed, executive function, and brain volumes were progressively smaller for a higher number of risk factors on target. These results were replicated in the Maastricht Study.Conclusions: Among individuals with diabetes, excess dementia risk, lower cognitive performance, and brain abnormalities decreased stepwise for a higher number of risk factors on target. [ABSTRACT FROM AUTHOR]

Many healthy individuals perceive themselves as forgetful and are interested in interventions to decrease their worries and increase their memory functioning. Educational interventions can be more effective when determinants are targeted that are known to predict perceived forgetfulness. In the present study, first, a broad range of determinants was selected from the literature and from experiences in clinical settings and, second, the most important determinants among the selected ones were identified with multivariate regression analyses. The study had a cross-sectional design. A sample of 300 healthy participants aged over 54 years filled in a self-report questionnaire. Findings indicated that low memory self-efficacy, high memory-related anxiety, negative attitude and high subjective norm (e.g. anticipating negative evaluations by important others) were the most important correlates of perceived forgetfulness. It is argued that future interventions should focus on the specified determinants to improve programme effectiveness in reducing subjective memory complaints. [ABSTRACT FROM AUTHOR]

• Blood-CSF barrier (BCSFB) function contributes to homeostasis in the interstitium. • How BCSFB disruption relates to age-related neurodegeneration is underassessed. • Contrast-enhanced MRI can be used to assess BCSFB permeability. • Post-contrast gadolinium enhancement in the ventricles can reveal BCSFB disruption. • New imaging techniques highly sensitive to CSF are promising for BCSFB assessment. VERHEGGEN, I.C.M., W. Freeze, J. de Jong, J. Jansen, A. Postma, M. van Boxtel, F. Verhey and W. Backes. The application of contrast-enhanced MRI in the assessment of blood-cerebrospinal fluid barrier integrity. Choroid plexus epithelial cells form a barrier that enables active, bidirectional exchange between the blood plasma and cerebrospinal fluid (CSF), known as the blood-CSF barrier (BCSFB). Through its involvement in CSF composition, the BCSFB maintains homeostasis in the central nervous system. While the relation between blood-brain barrier disruption, aging and neurodegeneration is extensively studied using contrast-enhanced MRI, applying this technique to investigate BCSFB disruption in age-related neurodegeneration has received little attention. This review provides an overview of the current status of contrast-enhanced MRI to assess BCSFB permeability. Post-contrast ventricular gadolinium enhancement has been used to indicate BCSFB permeability. Moreover, new techniques highly sensitive to low gadolinium concentrations in the CSF, for instance heavily T2-weighted imaging with cerebrospinal fluid suppression, seem promising. Also, attempts are made at using other contrast agents, such as manganese ions or very small superparamagnetic iron oxide particles, that seem to be cleared from the brain at the choroid plexus. Advancing and applying new developments such as these could progress the assessment of BCSFB integrity. [ABSTRACT FROM AUTHOR]

Background: Reductions in memory practice effects have gained interest as risk factor for future cognitive decline. Practice effects vary with age and can be moderated by factors such as individual variability in arousal or stress experience acting as an additional cognitive load.Objective: In the current pilot study, we examined whether sympathetic nervous system activation moderates the relationship between age and practice effects.Methods: Thirty cognitively healthy individuals aged 40-70 years performed a mnemonic discrimination task twice. Salivary alpha amylase (sAA) samples were obtained at different time points as a proxy of sympathetic activity. Spearman correlations examined the relation between practice effects and sAA. Subsequently, age by sAA interactions on practice scores were explored with bootstrapped linear regression models. Additionally, participants were divided in learners (exhibiting practice effects) and non-learners based on the difference in mnemonic discrimination performance.Results: Higher age and baseline SNS activity were independently related to lower practice effects. The non-learners showed significantly higher sAA scores at all time points compared to learners. Among the learners, baseline-adjusted lower levels of sAA after encoding were associated with greater practice effects, particularly in middle-aged individuals. No such interaction was observed for non-learners.Conclusion: These results show that higher baseline sympathetic activation is associated with worse practice effects independently of age. Additionally, in a subgroup of middle-aged learners practice effects were observed when sympathetic activity remained low during learning. These findings suggest that elevated sympathetic nervous system activation may be a promising indicator of imminent cognitive decline. [ABSTRACT FROM AUTHOR]

Informal caregivers are the primary source of support for adults with chronic conditions and disabilities. Empirical research highlights chronic stress and other risks of adverse outcomes of caregiving. Acceptance and Commitment Therapy (ACT) is an emerging evidenced-based practice that shows promise in improving an array of outcomes, theoretically by increasing psychological flexibility as the primary process of change. Research has begun to evaluate ACT among informal caregivers of adult populations, and a systematic review is now needed to summarise this evidence base. Electronic searches from five databases, including PubMed, PsycInfo, Embase, CINAHL, and Cochrane Library, yielded an initial 7896 hits, which after screening for inclusion criteria, resulted in 21 clinical trials. Studies were coded to synthesise the feasibility, effectiveness, and quality of evidence. Findings show that ACT was reported to be largely feasible and acceptable. However, the efficacy of ACT was mixed, with a more consistent pattern for informal caregivers of people with dementia. Several methodological quality issues limited the findings. However, theoretical synthesis and preliminary evidence support the promising effect of ACT in subgroups of informal caregivers. Research on the process of change, as well as larger-scale, methodologically rigorous trials, are needed to consolidate these findings. • ACT has been empirically evaluated for informal caregivers of adults with chronic conditions. • Limitations in the quality of studies were observed, but initial evidence is promising. • The implication of ACT in the context of caregiving is discussed. • More research is needed to consolidate findings in subgroups of caregivers. • Future research should focus on ACT process functioning and effectiveness in caregivers. [ABSTRACT FROM AUTHOR]

The kynurenine pathway is the main metabolic pathway of tryptophan degradation and has been associated with stroke and impaired cognitive functioning, but studies on its role in post-stroke cognitive impairment (PSCI) are scarce. We aimed to investigate associations between metabolites of the kynurenine pathway at baseline and post-stroke cognitive functioning over time. Baseline plasma kynurenines were quantified in 198 stroke patients aged 65.4 ± 10.8 years, 138 (69.7%) men, who were followed up over a period of three years after stroke. Baseline and longitudinal associations of kynurenines with PSCI and cognitive domain scores were investigated using linear mixed models, adjusted for several confounders. No evidence of associations between kynurenines and odds of PSCI were found. However, considering individual cognitive domains, higher plasma levels of anthranilic acid (AA) were associated with better episodic memory at baseline (β per SD 0.16 [0.05, 0.28]). Additionally, a linear-quadratic association was found for the kynurenic acid/ quinolinic acid ratio (KA/QA), a neuroprotective index, with episodic memory (Wald χ2 = 8.27, p =.016). Higher levels of KA were associated with better processing speed in women only (p interaction =.008; β per SD 0.15 [95% CI 0.02, 0.27]). These associations did not change over time. Higher levels of KA, AA and KA/QA were associated with better scores on some cognitive domains at baseline. These associations did not change over time. Given the exploratory nature and heterogeneity of findings, these results should be interpreted with caution, and verified in other prospective studies. • Higher levels of AA were associated with better episodic memory. • A linear-quadratic association was found of the KA/QA ratio with episodic memory. • Higher levels of KA were associated with better processing speed in women only. • These associations were present 3 months after stroke and did not change over time. • No evidence of associations between kynurenines and odds of PSCI was found. [ABSTRACT FROM AUTHOR]

Objective: Performance and symptom validity tests (PVTs and SVTs) measure the credibility of the assessment results. Cognitive impairment and apathy potentially interfere with validity test performance and may thus lead to an incorrect (i.e., false-positive) classification of the patient's scores as non-credible. The study aimed at examining the false-positive rate of three validity tests in patients with cognitive impairment and apathy. Methods: A cross-sectional, comparative study was performed in 56 patients with dementia, 41 patients with mild cognitive impairment, and 41 patients with Parkinson's disease. Two PVTs – the Test of Memory Malingering (TOMM) and the Dot Counting Test (DCT) – and one SVT – the Structured Inventory of Malingered Symptomatology (SIMS) – were administered. Apathy was measured with the Apathy Evaluation Scale, and severity of cognitive impairment with the Mini Mental State Examination. Results: The failure rate was 13.7% for the TOMM, 23.8% for the DCT, and 12.5% for the SIMS. Of the patients with data on all three tests (n = 105), 13.5% failed one test, 2.9% failed two tests, and none failed all three. Failing the PVTs was associated with cognitive impairment, but not with apathy. Failing the SVT was related to apathy, but not to cognitive impairment. Conclusions: In patients with cognitive impairment or apathy, failing one validity test is not uncommon. Validity tests are differentially sensitive to cognitive impairment and apathy. However, the rule that at least two validity tests should be failed to identify non-credibility seemed to ensure a high percentage of correct classification of credibility. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the cost-consequences of an intervention for the management of neuropsychiatric symptoms in nursing home residents with young-onset dementia.Methods: A stepped wedge design was used. The intervention consisted of an educational program and a multidisciplinary care program and was implemented in 13 nursing homes from September 2015 to March 2017. Costs' outcomes included the time investment of the elderly care physician and health care psychologists regarding the management of neuropsychiatric symptoms, residents' psychotropic drug use, nursing staff absenteeism, and costs of the educational program. Composite cost measure contained the sum of costs of staff absenteeism, costs on psychotropic drugs, and costs of the educational program. Costs of time investment were investigated by comparing means. Costs of psychotropic drug use were analyzed with mixed models at resident level and as part of the composite cost measure on unit level. Staff absenteeism was also analyzed at unit level.Results: Compared with care as usual, the mean costs of time invested decreased with €36.79 for the elderly care physician but increased with €46.05 for the health care psychologist in the intervention condition. Mixed model analysis showed no effect of the intervention compared with care as usual on the costs of psychotropic drug use, staff absenteeism, and the composite cost measure. The costs of the educational program were on average €174.13 per resident.Conclusion: The intervention did not result in increased costs compared with care as usual. Other aspects, such as the lack of a structured working method, should be taken into account when considering implementation of the intervention. [ABSTRACT FROM AUTHOR]

The APOE- ε4 genotype is a risk factor for late-onset Alzheimer's disease (AD) as well as vascular pathology. Given the increased risk of blood-brain barrier (BBB) dysfunction and inflammation among APOE- ε4 carriers, we aimed to examine whether BBB dysfunction and inflammation contribute to the relationship between APOE and AD key pathologies, as measured in the cerebrospinal fluid (CSF). We applied bootstrapped regression and path analyses involving Q-albumin CSF/plasma ratio (a BBB/blood-CSF barrier function marker), interleukins (IL-1β, IL-6, and IL-12p70; inflammation markers), and CSF p-Tau 181 and amyloid-β 1−42 (AD pathology markers) of 97 participants (aged 38–83 years) from a university memory clinic. Our results showed that relationship between BBB dysfunction and AD pathology is modulated by IL-6 and these associations appear to be driven by the APOE-ε4 genotype. This suggests that APOE-ε4-related vascular factors are also part of the pathway to AD pathology, in synergy with an elevated immune response, and could become targets for trials focused on delaying AD. • APOE- ε4 is a risk factor for late-onset Alzheimer's disease and vascular pathology. • Relation between blood-brain barrier dysfunction and Alzheimer's pathology. • Blood-brain/CSF barrier dysfunction and vascular are intertwined. • This relation appears to be driven by the APOE- ε4 status and modulated by IL-6. • APOE- ε4 and inflammation joined with vascular factors possible pathway to AD pathology. [ABSTRACT FROM AUTHOR]

• The AD biomarker - affective symptoms relationship shows inconsistent evidence. • Study designs assessing this relationship are very heterogeneous. • Majority of studies on depression show no relationship with AT(N) markers. • Future research should focus on possible subtypes of affective symptoms. Alzheimer's disease (AD) biomarkers such as amyloid, p-tau and neuronal injury markers have been associated with affective symptoms in cognitively impaired individuals, but results are conflicting. CINAHL, Embase, PsycINFO and PubMed were searched for studies evaluating AD biomarkers with affective symptoms in mild cognitive impairment and AD dementia. Studies were classified according to AT(N) research criteria. Forty-five abstracts fulfilled eligibility criteria, including in total 8,293 patients (41 cross-sectional studies and 7 longitudinal studies). Depression and night-time behaviour disturbances were not related to AT(N) markers. Apathy was associated with A markers (PET, not CSF). Mixed findings were reported for the association between apathy and T(N) markers; anxiety and AT(N) markers; and between agitation and irritability and A markers. Agitation and irritability were not associated with T(N) markers. Whereas some AD biomarkers showed to be associated with affective symptoms in AD, most evidence was inconsistent. This is likely due to differences in study design or heterogeneity in affective symptoms. Directions for future research are given. [ABSTRACT FROM AUTHOR]

Objectives: Previous studies have identified several subgroups (ie, latent trajectories) with distinct disease progression among people with dementia. However, the methods and results were not always consistent. This study aims to perform a coordinated analysis of latent trajectories of cognitive and functional progression in dementia across two datasets.Methods: Included and analyzed using the same statistical approach were 1628 participants with dementia from the US National Alzheimer's Coordinating Center (NACC) and 331 participants with dementia from the Dutch Clinical Course of Cognition and Comorbidity study (4C-Study). Trajectories of cognition and instrumental activities of daily living (IADL) were modeled jointly in a parallel-process growth mixture model.Results: Cognition and IADL tended to decline in unison across the two samples. Slow decline in both domains was observed in 26% of the US sample and 74% of the Dutch sample. Rapid decline in cognition and IADL was observed in 7% of the US sample and 26% of the Dutch sample. The majority (67%) of the US sample showed moderate cognitive decline and rapid IADL decline.Conclusions: Trajectories of slow and rapid dementia progression were identified in both samples. Despite using the same statistical methods, the number of latent trajectories was not replicated and the relative class sizes differed considerably across datasets. These results call for careful consideration when comparing progression estimates in the literature. In addition, the observed discrepancy between cognitive and functional decline stresses the need to monitor dementia progression across multiple domains. [ABSTRACT FROM AUTHOR]

Background: Differences in dementia risk across the gradient of socioeconomic status (SES) exist, but their determinants are not well understood.Objective: This study investigates whether health conditions and lifestyle-related risk factors explain the SES inequalities in dementia risk.Methods: 6,346 participants from the English Longitudinal Study of Ageing were followed up from 2008/2009 until 2014/2015. We used Cox regression adjusted for age, gender, wealth/education, and clustering at the household level to examine the association between SES markers (wealth, education) and time to dementia in a structural equation model including potential mediation or effect modification by a weighted compound score of twelve modifiable risk and protective factors for dementia ('LIfestyle for BRAin health' (LIBRA) score).Results: During a median follow-up of 6 years, 192 individuals (3.0%) developed dementia. LIBRA scores decreased with increasing wealth and higher educational level. A one-point increase in the LIBRA score was associated with a 13% increase in dementia risk (hazard ratio (HR) = 1.13, 95% confidence interval 1.07-1.19). Higher wealth was associated with a decreased dementia risk (HR = 0.58, 0.39-0.85). Mediation analysis showed that 52% of the risk difference between the highest and lowest wealth tertile was mediated by differences in LIBRA (indirect effect: HR = 0.75, 0.66-0.85). Education was not directly associated with dementia (HR = 1.05, 0.69-1.59), but was a distal risk factor for dementia by explaining differences in wealth and LIBRA scores (indirect effect high education: HR = 0.92, 0.88-0.95).Conclusion: Socioeconomic differences in dementia risk can be partly explained by differences in modifiable health conditions and lifestyle factors. [ABSTRACT FROM AUTHOR]

Neuropsychiatric symptoms are common in nursing home residents with young-onset dementia and burdensome for nursing staff. It is known that neuropsychiatric symptoms are associated with burn-out complaints and low job satisfaction. An intervention aimed at decreasing neuropsychiatric symptoms in nursing home residents with young-onset dementia might also result in less burnout complaints and job demands and improve job satisfaction in nursing staff. The aim was to evaluate the effect of the intervention on nursing staff burnout, job satisfaction and job demands. Cluster randomised controlled trial using a stepped wedge design with a total duration of 18 months, with four assessments. Thirteen young-onset dementia special care units across the Netherlands were, by means of random allocation software, assigned to three groups crossing over at different time points. All nursing staff, in total 391, were invited to participate. 305 nursing staff participated during the course of the study of whom 71 participated in all assessments. An educational program followed by a structured multidisciplinary care program aimed at the management of neuropsychiatric symptoms. The care program consists of evaluation of psychotropic drug prescription followed by detection, analysis, treatment and evaluation of treatment of neuropsychiatric symptoms. Emotional exhaustion, depersonalisation and personal accomplishment were assessed with the Utrecht Burnout Scale. Job satisfaction and job demands were assessed with subscales of the Leiden Quality of Work Questionnaire. The baseline burnout risk on emotional exhaustion and personal accomplishment was average, and low on depersonalisation. The mean scores for job satisfaction were above average and for job demands average. Linear mixed models showed that the intervention had no effect on emotional exhaustion (estimated effect −0.04, 95% confidence interval −1.25 to 1.16), depersonalisation (estimated effect 0.24, 95% confidence interval −0.26 to 0.74), personal accomplishment (estimated effect −0.82, 95% confidence interval −1.86 to 0.22) job satisfaction (estimated effect −0.40, 95% confidence interval −0.98 to 0.17) and job demands (estimated effect −0.04, 95% confidence interval −0.57 to 0.49). A significant difference was found between registered nurses and other nursing staff on emotional exhaustion and job satisfaction. Compared to other staff members, registered nurses' emotional exhaustion scores slightly increased while job satisfaction slightly decreased when using the intervention. The intervention was not effective on three dimensions of burnout, job satisfaction and job demands. Staff scored positive on the outcomes of interest before implementation of the intervention, leaving little opportunity for improvement. [ABSTRACT FROM AUTHOR]

Objectives: Memory clinics (MCs) have been established to improve diagnosis and treatment of cognitive disorders, including dementia. The aim of this study was to determine the characteristics and working methods of MCs in the Netherlands in 2016. More insight into different working methods can be used to improve the quality of care in Dutch MCs. Additionally, the findings will be compared with earlier results to investigate the development of MCs since 1998.Methods: A survey was sent in 1998, 2004, 2009, and 2017 to all operational Dutch MCs with questions about organization, collaboration, patients, and diagnostic procedures.Results: From 1998 to 2016, the number of MCs increased substantially from 12 to 91. The capacity increased from 1560 patients to 24,388. In 1998, most patients received a dementia diagnosis (85%), while in 2016, half of the patients were diagnosed with milder cognitive problems. MCs are more often part of regional care chains and are better embedded within regional care organizations. Diagnostic tools, such as blood tests (97%), neuropsychological assessment (NPA) (95%), and neuroimaging (92%), were used in nearly all MCs. The number of patients in whom these tools were used differed greatly between MCs (NPA: 5%-100%, neuroimaging: 10%-100%, and CSF: 0.5%-80%). There was an increase in the use of NPA, while the use of neuroimaging, CSF, and EEG/ECG decreased by 8% to 15% since 2009.Conclusions: Since 1998, MCs have developed substantially and outgrown the primarily research-based university settings. They are now accepted as regular care facilities for people with cognitive problems. [ABSTRACT FROM AUTHOR]

Objectives: Neuropsychiatric symptoms (NPSs) in dementia patients in nursing homes are common and often treated with psychotropic drugs. Thus far, studies on psychotropic drug use (PDU) mainly focused on elderly patients with dementia. It is important to know the prevalence and correlates of PDU in patients with young‐onset dementia (YOD) to optimize NPS treatment and reduce excess PDU in this group. Design The Behavior and Evolution in Young‐Onset Dementia (BEYOnD) study is a cross‐sectional study in 230 residents with YOD in eight nursing homes providing specialized YOD care. PDU was registered from medical charts. The influence of age, gender, severity, and type of dementia, NPS, and agitation on PDU was analyzed. Results: Eighty‐seven percent of the residents used psychotropic drugs, and 47% used two or more psychotropic drugs. No significant associations with age, gender, dementia subtype, and dementia severity were found. Depressive symptoms showed an association with the use of antidepressants, nighttime behavior with use of hypnotics, and verbal agitation with antipsychotics. Apathy was strongly associated with lower PDU. Conclusions: Nursing home patients with YOD have a high prevalence of PDU. The association with NPS raises questions of efficacy of these drugs in managing NPS. Patients with apathy had a lower chance of using psychotropics. More research on indications and effects of psychotropic drugs is needed, as well as on (nonpharmacological) alternatives for managing challenging behavior in YOD. [ABSTRACT FROM AUTHOR]

Background: Affective symptoms are considered a risk factor or prodromal symptom for dementia. Recent reviews indicate that depressive symptoms predict progression from mild cognitive impairment (MCI) to dementia, but results need to be further explored.Objective: To investigate the effect of depressive symptoms on the development of dementia in people with MCI, and explore potential sources of between-study variability, including study setting by a systematic review and meta-analysis.Methods: Databases were searched for prospective studies defining people with MCI at baseline, investigating dementia at follow-up and giving information about depressive symptoms. Two authors independently extracted data from the studies and rated the methodological quality. Meta-analyses were conducted using random-effect models to yield pooled risk ratios (RR). Meta-regression analyses tested differences between clinical and community-based studies and other sources of heterogeneity.Results: Thirty-five studies, representing 14,158 individuals with MCI, were included in the meta-analysis. Depressive symptoms in MCI predicted dementia in 15 community-based studies (RR = 1.69, 95% CI 1.49-1.93, I2 = 0.0%), but not in 20 clinical studies (RR = 1.02, 95% CI 0.92-1.14, I2 = 73.0%). Further investigation of this effect showed that the mean age of community-based studies was significantly higher than of clinical studies but neither this nor other study characteristics explained variability in study outcomes.Conclusions: Depressive symptoms are associated with an increased risk of conversion from MCI to dementia in community-based studies. In contrast, evidence in clinical populations was insufficient with high heterogeneity. [ABSTRACT FROM AUTHOR]

Highlights • APOE is not associated with affective symptoms in cognitively impaired subjects. • Studies assessing the affect-APOE relationship show large heterogeneity in design. • Contrasting prior findings could not be explained by this variation in study design. Abstract Objective APOE status has been associated to affective symptoms in cognitively impaired subjects, with conflicting results. Methods Databases CINAHL, Embase, PsychINFO and PubMed were searched for studies evaluating APOE genotype with affective symptoms in MCI and AD dementia. Symptoms were meta-analyzed separately and possible sources of heterogeneity were examined. Results Fifty-three abstracts fulfilled the eligibility criteria. No association was found between the individual symptoms and APOE ε4 carriership or zygosity. For depression and anxiety, only pooled unadjusted estimates showed positive associations with between-study heterogeneity, which could be explained by variation in study design, setting and way of symptom assessment. Conclusions There is no evidence that APOE ε4 carriership or zygosity is associated with the presence of depression, anxiety, apathy, agitation, irritability or sleep disturbances in cognitively impaired subjects. Future research should shift its focus from this single polymorphism to a more integrated view of other biological factors. [ABSTRACT FROM AUTHOR]

Objectives: The objectives of the study are to study daily hospital practice regarding detection and management and to study hyperactive and hypoactive delirium of older patients during their hospitalization.Methods: A retrospective cohort study evaluating care as usual for older hospitalized patients with delirium at Maastricht University Medical Center+, a university hospital in the Netherlands, was performed. Inclusion criteria were older hospitalized patients (65+ years), diagnosed with delirium between 1 January and 31 December 2014. Data were retrieved from the patients' medical files. Delirium was categorized as hyperactive or hypoactive. Primary outcome measures were prevalence and management (pharmacological, reorientation, screening for delirium and delirium consultations, and physical restraints). Secondary outcomes were short-term adverse outcomes.Results: Prevalence of delirium was 5% (N = 401), of which 77% (n = 307) was hyperactive and 23% (n = 94) was hypoactive. Significantly, more patients with a hyperactive delirium received medication to manage the delirium than patients with a hypoactive delirium (89% vs. 77%, respectively, p = 0.004). No other significant differences between the subtypes were found.Conclusion: There was probably a strong under-recognition of delirium. Drugs were the main intervention of choice, especially for patients with hyperactive delirium. The two subtypes did not differ on non-pharmacological management. The retrospective nature of this study sheds light on the status quo of recognition, management, and care as usual for the different delirium subtypes in daily hospital practice, which may help in forming new guidelines and protocols for the detection and treatment of delirium for older patients in hospitals. [ABSTRACT FROM AUTHOR]

Objectives A process evaluation was performed for an intervention aimed at improvement of the management of neuropsychiatric symptoms in young-onset dementia. Data about sample quality and intervention quality was evaluated to better understand internal and external validity. In addition, data about the implementation strategy and factors affecting implementation were evaluated to improve further implementation of the intervention. Design A model proposed by Leontjevas and colleagues consisting of first-order (validity) and second-order (implementation) data was used. Setting and Participants Care units delivering specialized treatment and support for residents with young-onset dementia. Measures A description of the recruitment, randomization procedure, and intervention reach was carried out to determine sample quality. To determine intervention quality, data on satisfaction, relevance, feasibility, and fidelity were collected through a questionnaire and reports logged on the server of the web-based intervention. A description of the implementation strategy was provided. Barriers and facilitators for implementation were collected by a questionnaire and analyzed by deductive content analysis. Results Care units varied in size and were recruited from different geographical regions in the Netherlands. The informed consent rate of the residents was 87.7%. The majority of the nursing home staff were satisfied with the intervention. However, parts of the intervention were perceived as less relevant for their own organization. The feasibility of the intervention was considered low. The fidelity differed between care units. The implementation strategy did not overcome all barriers. Factors affecting implementation covered 3 themes: organizational aspects, culture of the organization, and aspects of the intervention. Conclusions In general, our results showed sufficient internal and external validity, warranting further effect analyses. Adaptations to specific steps of the care program should be considered to increase feasibility and sustainability. In addition, integration of the care program into the electronic health records is expected to further improve implementation. [ABSTRACT FROM AUTHOR]

The underlying pathology of white matter signal abnormalities (WMSAs) is heterogeneous and may vary dependent on the magnetic resonance imaging contrast used to define them. We investigated differences in white matter diffusivity as an indicator for white matter integrity underlying WMSA based on T1-weighted and fluid-attenuated inversion recovery (FLAIR) imaging contrast. In addition, we investigated which white matter region of interest (ROI) could predict clinical diagnosis best using diffusion metrics. One hundred three older individuals with varying cognitive impairment levels were included and underwent neuroimaging. Diffusion metrics were extracted from WMSA areas based on T1 and FLAIR contrast and from their overlapping areas, the border surrounding the WMSA and the normal-appearing white matter (NAWM). Regional diffusivity differences were calculated with linear mixed effects models. Multinomial logistic regression determined which ROI diffusion values classified individuals best into clinically defined diagnostic groups. T1-based WMSA showed lower white matter integrity compared to FLAIR WMSA-defined regions. Diffusion values of NAWM predicted diagnostic group best compared to other ROI's. To conclude, T1- or FLAIR-defined WMSA provides distinct information on the underlying white matter integrity associated with cognitive decline. Importantly, not the “diseased” but the NAWM is a potentially sensitive indicator for cognitive brain health status. [ABSTRACT FROM AUTHOR]

Objective The aims of this study were (1) to investigate the relationship between different neuropsychiatric symptoms (NPS) and the level of distress experienced by nurses caring for residents with young-onset dementia (YOD) and (2) to compare these findings with those for nurses caring for residents with late-onset dementia (LOD). Design/Setting This is a retrospective study conducted in Dutch long-term care facilities. Data were used from the Behavior and Evolution of Young-ONset Dementia studies (BEYOND) Parts I and II and the WAAL Behavior in Dementia-II (Waalbed-II) study. Participants A total of 382 nursing home residents with YOD and 261 nursing home residents with LOD were included. Measurements The Neuropsychiatric Inventory, nursing home version, was used to assess nursing staff distress and the frequency (F) and severity (S) of NPS. Multilevel logistic regression analysis was used to investigate the relationships between nursing staff distress related to NPS and YOD and LOD care units, the F × S score per symptom, gender, dementia subtype, and dementia severity. Results Nurses working in YOD care units rated sleep and nighttime behavior disorders, delusions, and agitation/aggression most often as highly distressing and euphoria most often as not distressing. Multivariate analyses indicated that the frequency and severity of NPS were significantly associated with staff distress in all symptoms, except for apathy. Comparison of the 2 groups of nurses demonstrated that the odds for distress related to sleep and nighttime behavior disorders were higher for nurses in YOD care units than for nurses in LOD units. For both the YOD and LOD nurses, irritability in male residents had higher impact than similar behavior in female residents. Conclusion This study provides important insight into distress related to individual NPS and the interaction with residents' characteristics. All NPS result in distress. The frequency and severity of the behavior is an important predictor. Sleep and nighttime behavior disorders are more likely to result in distress in YOD nurses than in LOD nurses. The amount of distress related to NPS emphasizes the urgent need for adequate management of NPS and the support of professional caregivers. [ABSTRACT FROM AUTHOR]

Locus Coeruleus (LC) is a neuromelanin-rich brainstem structure that is the source of noradrenaline in the cortex and is thought to modulate attention and memory. LC imaging in vivo is commonly performed with a 2D T 1 -weighted Turbo Spin Echo (TSE) MRI sequence, an approach that suffers from several drawbacks at 3T, including long acquisition times and highly anisotropic spatial resolution. In this study, we developed a high-resolution Magnetization Transfer (MT) sequence for LC imaging at both 7T and 3T and compared its performance to a TSE sequence. Results indicate that LC imaging can be achieved with an MT sequence at both 7 and 3T at higher spatial resolution than the 3T TSE. Furthermore, we investigated whether the currently disputed source of contrast in the LC region with a TSE sequence relates to MT effects or shortened T 1 and T 2 * due to increased iron concentration. Our results suggest that the contrast in the LC area relates to MT effects. To conclude, in this study we managed to image the LC, for the first time, at 7T and at an increased resolution compared to the current state-of-the-art. Imaging the LC is highly relevant for clinical diagnostics as structural tissue properties of the LC may hold promise as a biomarker in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: Poststroke fatigue (PSF) is a form of pathological fatigue that can develop after stroke and has a negative impact on functional outcome. PSF is associated with poststroke depression (PSD), which in turn shows similarities with poststroke apathy (PSA). This study aimed at disentangling the temporal associations between PSF and PSD and between PSF and PSA. Methods: A total of 250 stroke patients were included, of which 243 completed the Fatigue Severity Scale, Montgomery-Åsberg Depression Rating Scale, and Apathy Evaluation Scale at 3 months poststroke, with follow-up measurements at 6 and 12 months after initial testing. Linear mixed models and linear regressions were performed to evaluate the temporal associations between PSF and PSD, and between PSF and PSA. Results: PSF was present in 119 patients (49%), of whom 62 patients also had PSD (26%), and 21 patients (9%) also had PSA. At baseline, PSF patients showed higher depression levels, which remained stable at follow-up. PSD patients had higher fatigue levels compared with no-PSD patients at baseline, which remained stable at follow-up. No association between apathy and fatigue was found at baseline and no interaction with time was found. Change in fatigue from baseline to 12-month follow-up was associated with change in depression and with change in apathy. Conclusions: Bidirectional associations were found between PSF and PSD. In treatment and rehabilitation programs, early focus on the presence of PSD and PSF is important, since these conditions tend to persist. As there are currently more treatment options for PSD, attention for PSD is important and might also have a beneficial effect on PSF. [ABSTRACT FROM AUTHOR]

Purpose Dynamic contrast-enhanced ( DCE) MRI can be used to measure blood-brain barrier ( BBB) leakage. In neurodegenerative disorders such as small vessel disease and dementia, the leakage can be very subtle and the corresponding signal can be rather noisy. For these reasons, an optimized DCE- MRI measurement and study design is required. To this end, a new measure indicative of the spatial extent of leakage is introduced and the effects of scan time and sample size are explored. Methods Dual-time resolution DCE- MRI was performed in 16 patients with early Alzheimer's disease ( AD) and 17 healthy controls. The leakage rate (Ki) and volume fraction of detectable leaking tissue ( vL) to quantify the spatial extent of BBB leakage were calculated in cortical gray matter and white matter using noise-corrected histogram analysis of leakage maps. Computer simulations utilizing realistic Ki histograms, mimicking the strong effect of noise and variation in Ki values, were performed to understand the influence of scan time on the estimated leakage. Results The mean Ki was very low (order of 10−4 min−1) and highly influenced by noise, causing the Ki to be increasingly overestimated at shorter scan times. In the white matter, the Ki was not different between patients with early AD and controls, but was higher in the cortex for patients, reaching significance after 14.5 min of scan time. To detect group differences, vL proved more suitable, showing significantly higher values for patients compared with controls in the cortex after 8 minutes of scan time, and in white matter after 15.5 min. Conclusions Several ways to improve the sensitivity of a DCE- MRI experiment to subtle BBB leakage were presented. We have provided vL as an attractive and potentially more time-efficient alternative to detect group differences in subtle and widespread blood-brain barrier leakage compared with leakage rate Ki. Recommendations on group size and scan time are made based on statistical power calculations to aid future research. [ABSTRACT FROM AUTHOR]

Aims: The aims of this study are to (1) explore the determinants of quality of life (QoL) in nursing home residents with young-onset dementia (YOD), (2) investigate whether there are differences between dementia subtypes (Alzheimer dementia, vascular/mixed dementia, frontotemporal dementia, other) regarding these determinants, and (3) compare QoL profiles of YOD nursing home residents across dementia subtypes. Methods: This cross-sectional study included 207 nursing home residents. Multilevel modeling was used to determine the relationships between QoL and neuropsychiatric symptoms (NPS), dementia severity, psychotropic drug use (PDU), dementia subtype, age, and gender. Additional multilevel models were used to compare aspects of QoL between dementia subtypes. Results: Residents' QoL was negatively associated with advanced dementia, PDU, and NPS. In general, the relationships between the determinants and QoL were similar across the dementia subtypes. Aspects of QoL differed by dementia subtype. Residents with frontotemporal dementia showed less negative emotions, accepted more help and experienced better quality of relationships with professional caregivers, had a more positive self-image, felt more comfortable in the nursing home environment, and experienced lower quality of social relationships. Conclusions: Considering the high rates of NPS and PDU in YOD residents and their negative associations with QoL, we recommend emphasizing services to manage and reduce NPS and PDU in nursing home residents with YOD. Furthermore, our findings suggest accounting for differences in aspects of QoL by dementia subtype to address specific needs and thereby improve QoL. [ABSTRACT FROM AUTHOR]

Aims Type 2 diabetes, hyperinsulinemia, and insulin resistance are associated with cognitive impairment. Experimental studies indicate that insulin signaling in the brain is related to cognitive performance. Here we evaluated whether insulin-related variables contribute to the variance in cognitive performance among individuals with type 2 diabetes. Methods A total of 806 individuals with type 2 diabetes (mean age 62 ± 8 years, HbA1c 6.9 ± 1.1%) completed a neuropsychological test battery. Insulin-related variables evaluated were: fasting plasma insulin, C-peptide, and the Homeostasis Model Assessment (HOMA2-IR; in individuals without insulin treatment; n = 641). The unadjusted coefficient of determination (R 2 ), obtained from multiple linear regression analyses, was used to estimate the proportion of variance in cognition explained by insulin-related variables. Results Sex, age, and educational level together explained 18.0% (R 2 ) of the variance in memory function, 26.5% in information processing speed, and 22.8% in executive function and attention. Fasting insulin, C-peptide, or HOMA2-IR did not increase the explained variance (maximum ΔR 2 0.3%, P ≥ 0.14). Similar results were obtained when insulin-related variables were added to models that additionally included glycemic control, cardiovascular risk factors, and depression. Conclusions Our results show that measures of peripheral insulin resistance are unrelated to cognitive performance among individuals with adequately controlled type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Promoting adaptation, improving well-being and maintaining an optimal quality of life (QOL) is an important aspect in dementia care. The purpose of this study was to identify determinants of QOL in young onset dementia, and to assess differences in QoL domains between people with Alzheimer's disease (AD) and frontotemporal dementia (FTD). Methods: In total 135 persons with AD and 58 persons with FTD were included from two prospective cohort studies. QOL was assessed with the proxy reported quality of life in Alzheimer's disease questionnaire (QoL-AD). Possible determinants were explored using multiple linear regression and included sociodemographic variables, diagnosis, dementia severity, disease awareness, neuropsychiatric symptoms, met and unmet needs and hours of personal and instrumental care. Differences between QOL domains in people with AD and FTD were calculated using Mann-Whitney U tests. Results: Lower QOL was associated with more depressive symptoms, lower disease awareness, and a higher amount of needs, both met and unmet. People with AD scored lower on the memory and higher on the friends' subscale. No differences were found for the other items. Conclusion: This study demonstrates a unique set of determinants of QOL in AD and FTD. Interventions directed towards these specific factors may improve QOL. [ABSTRACT FROM AUTHOR]

Objective: Delirium is a serious and common complication among older hospitalized patients and is a predictor of many adverse outcomes. However, up to 72% of delirium incidents are unrecognized or misdiagnosed. The aim of this systematic review is to determine the validity, reliability, and feasibility of instruments for the detection of delirium in older hospitalized patients.Methods: A systematic literature search was conducted. The inclusion criteria were a mean or median age of 65+ years, the use of the Diagnostic and Statistical Manual of Mental Disorders or International Classification of Diseases-10 as a reference standard, and publication in English. All included studies underwent a quality assessment (QUADAS-2).Results: Forty-three of the 3.790 identified studies were relevant to the review, describing 28 instruments. Quality assessment resulted in 37 studies with a positive quality assessment, describing 23 instruments. Five instruments (Delirium Observation Scale (DOS), Nursing Delirium Screening Scale (Nu-DESC), Confusion Assessment Method (CAM), CAM-Intensive Care Unit (ICU), and Delirium Rating Scale-Revised-98) were described in three or more methodologically sound studies. The Delirium Observation Screening Scale (DOS) and Nu-DESC are observational instruments with good psychometric properties, but the Nu-DESC is shorter and has been validated in more languages. The CAM, CAM-ICU, and Delirium Rating Scale-Revised-98 (DRS-R-98) are instruments with both observational and interactive components. The CAM is the most widely studied and demonstrates the best psychometric properties.Conclusion: Timely detection of delirium might reduce the negative outcomes of delirium in the long term. The Nu-DESC and CAM appear to be the most adequate instruments for detecting delirium. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]