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Aims/hypothesis: Studies investigating associations between kynurenines and cognitive function have generally been small, restricted to clinical samples or have found inconsistent results, and associations in the general adult population, and in individuals with type 2 diabetes in particular, are not clear. Therefore, the aim of the present study was to investigate cross-sectional associations between plasma kynurenines and cognitive function in a cohort of middle-aged participants with normal glucose metabolism, prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes., Methods: Plasma kynurenines were quantified in 2358 participants aged 61 ± 8 years. Cross-sectional associations of kynurenines with cognitive impairment and cognitive domain scores were investigated using logistic, multiple linear and restricted cubic spline regression analyses adjusted for several confounders., Results: Effect modification by glucose metabolism status was found for several associations with cognitive impairment, hence analyses were stratified. In individuals with prediabetes, 3-hydroxykynurenine (OR per SD 0.59 [95% CI 0.37, 0.94]) and 3-hydroxyanthranilic acid (0.67 [0.47, 0.96]) were associated with lower odds of cognitive impairment after full adjustment. In individuals with type 2 diabetes, kynurenine (0.80 [0.66, 0.98]), 3-hydroxykynurenine (0.82 [0.68, 0.99]), kynurenic acid (0.81 [0.68, 0.96]), xanthurenic acid (0.73 [0.61, 0.87]) and 3-hydroxyanthranilic acid (0.73 [0.60, 0.87]) were all associated with lower odds of cognitive impairment. Kynurenic acid (β per SD 0.07 [95% CI 0.02, 0.13]) and xanthurenic acid (0.06 [0.01, 0.11]) were also associated with better executive function/attention. No associations were observed in individuals with normal glucose metabolism., Conclusions/interpretation: Several kynurenines were cross-sectionally associated with lower odds of cognitive impairment and better cognitive functioning in type 2 diabetes, while less widespread associations were seen in prediabetes. Low levels of kynurenines might be involved in the pathway of type 2 diabetes and cognitive decline but this needs further studies., (© 2021. The Author(s).)

Background and Purpose- Type 2 diabetes mellitus (T2D) is associated with cognitive impairment and an increased risk of dementia, but the association between prediabetes and cognitive impairment is less clear, particularly in a setting of major cerebrovascular events. This article examines the impact of impaired fasting glucose and T2D on cognitive performance in a stroke population. Methods- Seven international observational studies from the STROKOG (Stroke and Cognition) consortium (n=1601; mean age, 66.0 years; 70% Asian, 26% white, and 2.6% African American) were included. Fasting glucose level (FGL) during hospitalization was used to define 3 groups, T2D (FGL ≥7.0 mmol/L), impaired fasting glucose (FGL 6.1-6.9 mmol/L), and normal (FGL <6.1 mmol/L), and a history of diabetes mellitus and the use of a diabetes mellitus medication were also used to support a diagnosis of T2D. Domain and global cognition Z scores were derived from standardized neuropsychological test scores. The cross-sectional association between glucose status and cognitive performance at 3 to 6 months poststroke was examined using linear mixed models, adjusting for age, sex, education, stroke type, ethnicity, and vascular risk factors. Results- Patients with T2D had significantly poorer performance in global cognition (SD, -0.59 [95% CI, -0.82 to -0.36]; P <0.001) and in all domains compared with patients with normal FGL. There was no significant difference between impaired fasting glucose patients and those with normal FGL in global cognition (SD, -0.10 [95% CI, -0.45 to 0.24]; P =0.55) or in any cognitive domain. Conclusions- Diabetes mellitus, but not prediabetes, is associated with poorer cognitive performance in patients 3 to 6 months after stroke.

The mechanisms underlying cognitive impairment are incompletely understood but may include arterial stiffness and microvascular dysfunction. In the population-based Maastricht Study, we investigated the association between arterial stiffness and cognitive performance, and whether any such association was mediated by microvascular dysfunction. We included cross-sectional data of 2544 participants (age, 59.7 years; 51.0% men; 26.0% type 2 diabetes mellitus). We used carotid-femoral pulse wave velocity and carotid distensibility coefficient as measures of aortic and carotid stiffness, respectively. We calculated a composite score of microvascular dysfunction based on magnetic resonance imaging features of cerebral small vessel disease, flicker light-induced retinal arteriolar and venular dilation response, albuminuria, and plasma biomarkers of microvascular dysfunction (sICAM-1 [soluble intercellular adhesion molecule-1], sVCAM-1 [soluble vascular adhesion molecule-1], sE-selectin [soluble E-selectin], and vWF [von Willebrand factor]). Cognitive domains assessed were memory, processing speed, and executive function. A cognitive function score was calculated as the average of these domains. Higher aortic stiffness (per m/s) was associated with lower cognitive function (β, -0.018 SD [95% CI, -0.036 to -0.000]) independent of age, sex, education, and cardiovascular risk factors, but higher carotid stiffness was not. Higher aortic stiffness (per m/s) was associated with a higher microvascular dysfunction score (β, 0.034 SD [95% CI, 0.014 to 0.053]), and a higher microvascular dysfunction score (per SD) was associated with lower cognitive function (β, -0.089 SD [95% CI, -0.124 to -0.053]). Microvascular dysfunction significantly explained 16.2% of the total effect of aortic stiffness on cognitive function. The present study showed that aortic stiffness, but not carotid stiffness, is independently associated with worse cognitive performance, and that this association is in part explained by microvascular dysfunction.

Microvascular dysfunction may be associated with worse cognitive performance. Most previous studies did not adjust for important confounders, evaluated only individual measures of microvascular dysfunction, and showed inconsistent results. We evaluated the association between a comprehensive set of measures of microvascular dysfunction and cognitive performance in the population-based Maastricht Study. We used cross-sectional data including 3011 participants (age 59.5±8.2; 48.9% women; 26.5% type 2 diabetes mellitus [oversampled by design]). Measures of microvascular dysfunction included magnetic resonance imaging features of cerebral small vessel disease, plasma biomarkers of microvascular dysfunction, albuminuria, flicker light-induced retinal arteriolar and venular dilation response and heat-induced skin hyperemia. These measures were summarized into a microvascular dysfunction composite score. Cognitive domains assessed were memory, processing speed, and executive function. A cognitive function score was calculated as the sum of the scores on these 3 cognitive domains. The microvascular dysfunction score was associated with a worse cognitive function score (standardized β, -0.087 [95% CI, -0.127 to -0.047]), independent of age, education level, sex, type 2 diabetes mellitus, smoking, alcohol use, hypertension, total/HDL (high-density lipoprotein) cholesterol ratio, triglycerides, lipid-modifying medication, prior cardiovascular disease, depression and plasma biomarkers of low-grade inflammation. The fully adjusted β-coefficient of the association between the microvascular dysfunction score and the cognitive function score was equivalent to 2 (range, 1-3) years of aging for each SD higher microvascular dysfunction score. The microvascular dysfunction score was associated with worse memory and processing speed but not with worse executive function. The present study shows that microvascular dysfunction is associated with worse cognitive performance.

An increasing number of individuals will face age-related cognitive difficulties because life expectancy has increased. It is, therefore, important to identify modifiable risk factors for cognitive impairment. Very short-term to mid-term blood pressure variability (BPV) may be such a factor because it may cause cerebral ischemia. To this end, we investigated whether greater systolic and diastolic BPV are cross-sectionally associated with memory function (n=1804), information processing speed (n=1793), and executive function (n=1780) in 40- to 75-year-old individuals from The Maastricht Study. A composite BPV-index was derived by standardizing within-visit, 24-hour, and 7-day BPV. We performed linear regression with adjustments for age, sex, educational level, 24-hour systolic or diastolic pressure, and cardiovascular risk factors. We found that a 1-SD greater systolic BPV was not associated with information processing speed (β [SD difference], -0.10; 95% CI, -0.14 to 0.06), or executive function (-0.09; 95% CI, -0.20 to 0.02) but was marginally associated with lower memory function (-0.11; 95% CI, -0.21 to 0.00). A 1-SD greater diastolic BPV was associated with lower information processing speed (-0.10; 95% CI, -0.20 to -0.00) and executive function (-0.12; 95% CI, -0.22 to -0.01) and marginally associated with lower memory function (-0.09; 95% CI, -0.20 to 0.01). These effects on cognitive performance are equivalent to ≈3 additional years of aging. In conclusion, greater very short-term to mid-term diastolic and, to a lesser extent, systolic BPV may be a modifiable risk factor for cognitive deterioration in 40- to 75-year-old, community-dwelling individuals.

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., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

ABSTRACTBackground:Dementia is a neurodegenerative syndrome that interferes with multiple aspects of life, including cognition, daily functioning, and behavior. Despite the large heterogeneity in symptom development, these three domains are seldom studied simultaneously. This study investigates how trajectories of these domains are interrelated within individuals over time, and how they in turn are related to dementia severity and quality of life (QoL)., Methods: We used data from a longitudinal clinical cohort study, including 331 dementia patients. Cognitive status was measured using the Mini-Mental State Examination, daily functioning was measured with the disability assessment for dementia and neuropsychiatric symptoms (NPS) were scored using the neuropsychiatric inventory. We investigated the relationships in the time course of the various dementia domains using random effects multilevel models and parallel-process growth models., Results: Changes in cognition and daily functioning were highly correlated over time (r = 0.85, p < 0.01), as were changes in NPS and functioning (r = -0.60, p < 0.01), while changes in cognition and NPS were not (r = -0.20, p = 0.06). All three domains were strongly associated with dementia severity over time (p < 0.01). Decreased functioning and increased NPS were both associated with decreased QoL (β = 2.97, p < 0.01 and β = -2.41, p < 0.01, respectively), while cognition was not (β = 0.01, p = 0.93)., Conclusion: This study demonstrates the heterogeneity of dementia progression between individuals and between different dementia domains within individuals. To improve our understanding of dementia progression, future research should embrace a broader perspective encompassing multiple outcome measures along with the patient's profile, including neurological factors as well as physical, social, and psychiatric health.

Objective: To study to what extent differences in cognitive performance between individuals with different glucose metabolism status are potentially attributable to hyperglycemia, insulin resistance, and blood pressure-related variables., Research Design and Methods: We used cross-sectional data from 2,531 participants from the Maastricht Study (mean age ± SD, 60 ± 8 years; 52% men; n = 666 with type 2 diabetes), all of whom completed a neuropsychological test battery. Hyperglycemia was assessed by a composite index of fasting glucose, postload glucose, glycated hemoglobin (HbA 1c ), and tissue advanced glycation end products; insulin resistance by the HOMA of insulin resistance index; and blood pressure-related variables included 24-h ambulatory pressures, their weighted SDs, and the use of antihypertensive medication. Linear regression analyses were used to estimate mediating effects., Results: After adjustment for age, sex, and education, individuals with type 2 diabetes, compared with those with normal glucose metabolism, performed worse in all cognitive domains (mean differences in composite z scores for memory -0.087, processing speed -0.196, executive function and attention -0.182; P values <0.032), whereas individuals with prediabetes did not. Diabetes-associated differences in processing speed and executive function and attention were largely explained by hyperglycemia (mediating effect 79.6% [bootstrapped 95% CI 36.6; 123.4] and 50.3% [0.6; 101.2], respectively) and, for processing speed, to a lesser extent by blood pressure-related variables (17.7% [5.6; 30.1]), but not by insulin resistance. None of the factors explained the differences in memory function., Conclusions: Our cross-sectional data suggest that early glycemic and blood pressure control, perhaps even in the prediabetic stage, may be promising therapeutic targets for the prevention of diabetes-associated decrements in cognitive performance., (© 2017 by the American Diabetes Association.)

Background: The aim of the study was to evaluate whether adding a geriatric nurse practitioner (GNP) to an outpatient diagnostic multidisciplinary facility for patients with cognitive disorders (Diagnostic Observation Center for PsychoGeriatry, DOC-PG) could improve quality of care. DOC-PG combines hospital diagnostics and care assessment from a community mental health team and provides the general practitioner (GP) with advice for treatment and management. In a previous study, we found that 28.7% of the advice made by this service was not followed up on by the GP., Methods: Two cohorts were studied: a group of patients with added GNP (n = 114) and a historical reference sample (n = 137). Both groups followed the same diagnostic protocol and care approach, but, in the GNP group, a care coordinator was added in order to communicate the advice from the DOC-PG to the GP. The primary outcome was the concordance rate of GPs regarding the advice. At the patient level, health-related quality of life (HRQoL) was assessed. Self-Rated Burden and care-related quality of life were measured at the informal caregiver level. Measures were conducted immediately after DOC-PG diagnosis and after 6 and 12 months. Univariate analyses, logistic regression analyses, and mixed model multilevel analyses were used to test differences between both groups., Results: Total concordance rates were significantly higher in the GNP group compared to the reference sample (82.1 and 71.3%, respectively; p < 0.001). No improvement in patient HRQoL was identified. Among the informal caregivers, a significant reduction of Self-Rated Burden was found in the GNP group at 12 months (adjusted mean difference -1.724, 95% CI -2.582 to -0.866; p < 0.001)., Conclusions: Adding a GNP to an outpatient diagnostic multidisciplinary facility for patients with cognitive disorders may improve the GP concordance rate of the advice from the DOC-PG and reduce subjective burden of the informal caregiver.

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 © 2012 Elsevier B.V. All rights reserved.)

Objectives: To examine the temporal association between depressive symptoms and cognitive functioning and estimate the effect measure modification of the apolipoprotein E (APOE) epsilon4 allele on this relationship., Design: Prospective cohort study., Setting: General community., Participants: Population-based sample of 598 cognitively intact older adults aged 60 and older, with re-assessments after 3 (N=479) and 6 years (N=412)., Measurements: Depressive symptoms (Symptom Checklist) and neurocognitive functioning (memory, Visual Verbal Learning Test; attention, Stroop Color-Word Test; processing speed, Letter Digit Substitution Test; general cognition, Mini-Mental State Examination). Longitudinal associations were assessed using linear mixed models. The risk for cognitive impairment, no dementia (CIND) was examined using logistic regression., Results: Adjusting for age, sex, education, and baseline cognition, the rate of change in memory z-scores was 0.00, -0.11, -0.20, and -0.37 for those in the lowest (reference group), second, third, and highest depressive symptom quartiles at baseline, respectively (P<.001 for highest vs lowest quartile). The odds ratios for developing CIND with amnestic features were 1.00, 0.87, 0.69, and 2.98 for the four severity groups (P=.05 for highest vs lowest quartile). Associations were strongest for those with persistent depressive symptoms, defined as high depressive symptoms at baseline and at least one follow-up visit. Results were similar for processing speed and global cognitive function but were not as strong for attention. No APOE interaction was observed., Conclusion: Depression and APOE act independently to increase the risk for cognitive decline and may provide targets for prevention and early treatment.

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.

Background: Parkinson disease (PD) is a neuropsychiatric disease that is characterized by motor and neuropsychiatric symptoms. Multiple neurotransmitter systems, including the serotonergic system, are involved in the pathophysiology of this disease. The exact role of the serotonergic system in PD is still unclear., Objective: To investigate the role of serotonin on specific aspects of cognition, mood, and motor performance in PD., Methods: In a double-blind, randomized, placebo-controlled, crossover design, the effects of a nonspecific serotonergic challenge with citalopram, a selective serotonin reuptake inhibitor, and a 5-HT1a receptor-specific challenge with buspirone on the Visual Verbal Learning Task, Concept Shifting Task, Profile of Mood State Questionnaire, motor section of the Unified Parkinson Disease Rating Scale (section 3), Simple Reaction Time Task, and Finger Precuing Task were studied in 21 PD patients in early stages of their disease and 21 age-, sex-, and education-matched healthy volunteers., Results: The serotonergic challenges resulted in similar effects for both groups. No changes of scores on the cognitive tasks (Visual Verbal Learning Task and Concept Shifting Task) were observed. Results of the Profile of Moods State Questionnaire indicated that, at baseline, PD patients scored less than controls on all 5 subscales. Motor performance (measured by reaction time) was negatively affected by the interventions., Conclusions: The effects of nonspecific and 5-HT1a receptor-specific challenging of the serotonergic neurotransmitter system had similar effects in both PD patients and healthy control subjects. These findings indicate that serotonergic function is not impaired in early PD and that serotonin, although involved in the pathophysiology of PD, does not seem to play a direct role in cognition, mood, and motor performance in PD patients, but may be involved in hypokinesia.

Background: Spousal caregivers are usually of the same age as the dementia patient and therefore at risk of age-related cognitive decline. Suboptimal cognitive functioning in caregivers may have profound implications., Methods: Fifty-four spousal caregivers of dementia patients from the Memory Clinic of the Academic Hospital Maastricht and the Regional Institute for Community Mental Health Care in the Netherlands were compared with 108 non-caregiving controls. Data were collected on patient and caregiver characteristics and caregiver cognitive functioning. Repeated measures statistical analyses were carried out to investigate the relationship between caregiver cognitive functioning at baseline and patient behavioural problems and caregiver competence during 1 year of follow-up., Results: Caregivers performed significantly worse on several cognitive domains compared with control subjects. Low performance on a verbal memory task was related to a decrease in caregiver subjective competence and an increase in patient hyperactivity., Conclusion: The results indicate that screening for cognitive impairment of spousal caregivers may be helpful, because suboptimal cognitive functioning may affect the ability to provide adequate care.

Background: Transnational and psychometrically appropriate versions of instruments used in the diagnosis of dementia are essential for comparing information between different countries. The Cambridge Examination for Mental Disorders of the Elderly incorporates a brief neuropsychological test battery, Cambridge Cognitive Examination (recently revised version), which provides objective data on performance across a number of cognitive domains., Objective: To harmonise the Cambridge Cognitive Examination between seven European countries., Method: 40 patients with probable or possible Alzheimer's disease of each of the seven countries were administered the Cambridge Cognitive Examination. The Nurse Observation Scale for Geriatrics was used to assess concordance between cognitive and behavioural measures., Results: Only small differences between the various Cambridge Cognitive Examination versions were found, and patterns of correlation between Cambridge Cognitive Examination and the Nurse Observation Scale for Geriatrics were consistent., Conclusion: These findings indicate that the harmonisation of the Cambridge Cognitive Examination was successful.

Aims Cardiovascular disease (CVD) has been suggested to accelerate cognitive decline and to be a risk factor for dementia, but still little is known about the cognitive course after a first cardiovascular event. Therefore, the present study aims to investigate the cognitive trajectories in both prevalent and incident CVD over a 12-year time period in the general population. Methods and results Cognitively healthy participants (age 24–82 years, n  = 1823) of a prospective cohort study were serially assessed at baseline, 6 and 12 years. Verbal memory, executive function, and information processing speed were analysed in adults with prevalent, incident, and no CVD. Random effects models were used to test the association between CVD and change in cognitive function over time. At baseline, participants with prevalent CVD showed more decline in memory and information processing speed than healthy controls. Participants with incident CVD also showed more decline in these cognitive domains, but this was only significant in the follow-up period from 6 to 12 years. Associations were more pronounced in participants aged younger than 65 years at baseline, and in sub-analyses with angina pectoris or myocardial infarction as the most prevalent CVD conditions. Conclusion Prevalent and incident CVD predict cognitive decline in middle-aged individuals. Findings for incident CVD suggest that the onset of decline is linked in time with the vascular event itself. Timely CVD management may delay the onset of decline. [ABSTRACT FROM AUTHOR]

Background: Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD).Objective: To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype.Methods: From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42, total (t-)Tau, and phosphorylated (p-)Tau.Results: CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient -0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029).Conclusion: Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus is associated with accelerated cognitive decline and various cerebral abnormalities visible on MRI. The exact pathophysiological mechanisms underlying cognitive decline in diabetes still remain to be elucidated. In addition to conventional images, MRI offers a versatile set of novel contrasts, including blood perfusion, neuronal function, white matter microstructure, and metabolic function. These more-advanced multiparametric MRI contrasts and the pertaining parameters are able to reveal abnormalities in type 2 diabetes, which may be related to cognitive decline. To further elucidate the nature of the link between diabetes, cognitive decline, and brain abnormalities, and changes over time thereof, biomarkers are needed which can be provided by advanced MRI techniques. This review summarizes to what extent MRI, especially advanced multiparametric techniques, can elucidate the underlying neuronal substrate that reflects the cognitive decline in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Heterogeneous disease trajectories of mild cognitive impairment (MCI) and dementia are frequently encountered in clinical practice, but there is still insufficient knowledge to understand the reasons and mechanisms causing this heterogeneity. In addition to correlates of the disorder, patient characteristics such as their health status, social environment, comorbidities and frailty may contribute to variability in trajectories over time. The current paper outlines the study design and the study population of and provides an overview of the data collected in the Clinical Course of Cognition and Comorbidity in Mild Cognitive Impairment (4C-MCI cohort, n = 315) and Dementia (4C-Dementia cohort, n = 331) Study. Methods: The two complementary longitudinal cohorts part of the 4C study began enrolment in March 2010. Participants were prospectively recruited from three collaborating Dutch Alzheimer Centers, with three annual follow-up assessments after baseline. Extensive neuropsychological assessments, and detailed profiling of comorbidities, health and frailty at each follow up were the key features of the 4C study. As such, the 4C study was designed to study if and how patients' comorbidities and frailty are associated with the course of MCI and dementia measured with a comprehensive and multidimensional set of outcomes including cognition, daily functioning, quality of life, behavioral disturbances, caregiver burden, institutionalization and death and whether the effects of medical health and frailty differ between MCI and dementia stages of cognitive disorders. Conclusion: Sampled in a clinical setting, the 4C study complements population-based studies on neurodegenerative disorders in terms of the type of assessment (e.g. comorbidity, frailty, and functional status were repeatedly assessed). The 4C study complements available clinical cohorts of MCI and dementia patients, because the exclusion criteria were kept to a minimum, to obtain a sample that is representative for the average patient visiting a memory clinic. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairment and neuropsychiatric syndromes, like depression and apathy, are frequent residual consequences of stroke. These have a large impact on quality of life and long-term prognosis. Several factors are involved in the development of these residual syndromes, although their exact role and their interrelationships remain still rather unclear. The Cognition and Affect after Stroke: a Prospective Evaluation of Risks (CASPER) study has been primarily designed to examine whether stroke-specific (e.g. lesion location, volume, type, severity), cerebrovascular and neurodegenerative (e.g. white matter changes, atrophy, microbleeds, perivascular spaces), inflammatory, endothelial, and (epi)genetic markers are associated with cognitive impairment, post-stroke depression, and post-stroke apathy, and whether they predict their course over 12 months. The secondary aims are to investigate how the above-mentioned markers interact with each other, and to determine if patients with apathy and depression after stroke differ in pathogenesis, course, and outcome (e.g. functional outcome, neurocognitive performance, quality of life). Methods/design: CASPER is a 1-year prospective clinical cohort follow-up study in 250 stroke patients recruited at the neurological in- and outpatient services at Maastricht University Medical Center (MUMC+, Maastricht, The Netherlands), and Zuyderland Medical Center (Sittard and Heerlen, The Netherlands). At baseline (3 months post-stroke), a neuropsychological assessment, neuropsychiatric interview, blood sample, and brain magnetic resonance imaging (MRI) scan are conducted. Assessment of neuropsychiatric and neurocognitive status are repeated 6 and 12 months later. Discussion: The CASPER study investigates stroke-specific, vascular, neurodegenerative, inflammatory, and genetic markers of the development of vascular cognitive impairment, depression, and apathy after stroke. This creates the possibility to study not only the contribution of these individual markers but also their joint contribution, which differentiates this study from earlier stroke cohorts who lacked long-term follow-up data, a large sample size, an extensive MRI protocol, and markers from the blood. The knowledge we derive from this study might help in identifying markers that are associated with, or can predict the onset, maintenance, and progression of vascular cognitive impairment, depression, and apathy after stroke, and could provide new insights into possibilities for treatment and rehabilitation that result in better functional outcome after stroke. Trial Registration: ClinicalTrials.gov NCT02585349. [ABSTRACT FROM AUTHOR]

Background: The relation between psychological distress, personality traits, and cognitive decline in cognitively impaired patients remains unclear.Objective: To investigate the effect of psychological distress and personality traits on cognitive functioning in subjects with mild cognitive impairment (MCI); and to investigate the predictive accuracy of these factors for the development of dementia.Methods: MCI patients (n = 343, age: 60.9±9.9 years, 38% female, and MMSE score: 28.1±1.9) were included from the Maastricht memory clinic. All patients underwent a standardized neuropsychological assessment (including tests for measuring mental speed (Trail Making Test (TMT) part A and Stroop Color Word Test (SCWT) part I), executive functioning (TMT part B and SCWT part III), memory (15-Word Learning Tests), and verbal fluency (1-minute animals)), CT or MRI, and blood assessment. The Dutch Personality Questionnaire (DPQ) and the 90-items Symptom Check List (SCL-90) were used to measure personality traits and psychological distress. Conversion to dementia was assessed two, five, and ten years after baseline. The mean follow-up period was 6.7±3.4 years.Results: The Psychoneuroticism score of the SCL-90 was associated with slower performances on SCWT part I and TMT part A. The subdomain Neuroticism of the DPQ was also associated with slower scores on the TMT part A. At follow-up, 85 (25.9%) subjects had developed dementia. The SCL-90 total score, and the subscales, Anxiety, Somatization, Insufficiency in thought and action, and Sleeping problems were associated with a decreased risk for developing (AD-type) dementia.Conclusion: Psychological distress negatively affected information processing speed, but was not associated with an increased risk of developing dementia in patients with MCI. [ABSTRACT FROM AUTHOR]

Midlife hypertension is a risk factor for dementia, but little is known about the cognitive trajectories of individuals with incident hypertension. This study follows the cognitive functioning in prevalent and incident hypertension for 12 years and in relation to age and treatment status. Cognitively intact adults aged 25 to 84 years (n=1805) were serially assessed at baseline, 6 years, and 12 years. Hypertension was defined by sphygmomanometry or antihypertensive medication use, and its association with cognitive decline was tested in random-effects models. At baseline, 638 (35.3%) participants had hypertension. They showed faster decline in memory (χ² test for homogeneity=35.75; df=-2; P<0.001), executive functions (χ²=21.68; df=-2; P<0.001), and information processing speed (χ²=81.96; df=- 2; P<0.001) than baseline normotensive participants. At follow-up, 352 individuals (30.2%) developed incident hypertension. They showed faster decline in memory (χ²=7.88; df=-2; P=0.019) and information processing speed (χ²= 18.06; df=-2; P<0.001), especially from 6- to 12-year follow-up. Effects were most pronounced and widespread in midlife for both prevalent and incident hypertension and in those with untreated and uncontrolled hypertension. This study shows that incident hypertension predicts cognitive decline in middle-aged individuals, and those with poorly controlled blood pressure are most at risk. In newly diagnosed individuals, decline evolves gradually, possibly opening a window for early intervention. [ABSTRACT FROM AUTHOR]

Objectives: To study the temporal association between psychotic symptoms with cognitive decline and incident dementia. Design: Population-based prospective cohort study. Setting: General population in England and Wales. Participants: A subsample of 2,025 participants of the Medical Research Council Cognitive Function and Ageing Study, representing a study sample of 11,916 nondemented adults age 65 years or older. Measurements: Baseline presence of psychotic symptoms was assessed with the Geriatric Mental State. Cognitive decline (Cambridge Cognitive Examination) and incident dementia (Automated Geriatric Examination for Computer Assisted Taxonomy diagnosis) were evaluated at 2, 6, and 10 years from baseline. Results: A total of 330 participants reported baseline symptoms of paranoid delusions, misidentification, or hallucinations, estimated to represent 13.4% of the older general population without dementia. Psychotic symptoms were cross- sectionally associated with worse cognitive functioning, and individuals with psychotic symptoms displayed more rapid cognitive decline from baseline to a 6-year follow-up, especially in nonmemory functions, than people without such symptoms. TheF further carried an increased overall risk of later dementia (odds ratio = 2. 76, 95% confidence interval = 1.75-4.36). The risk increment was observed independently of baseline cognition, depression, anxiety, and vascular risk factors, increased with increasing numbers of psychotic symptoms, and was highest in people age 65-74 years. Conclusions: Older adults with psychotic symptoms are vulnerable to develop dementia and might be a promising target for indicated prevention strategies. Their neuropsychological functioning should be evaluated on a regular basis. [ABSTRACT FROM AUTHOR]

Objective: To study the impact of physical and mental fatigue on cognitive complaints and cognitive performance in patients with multiple sclerosis. Design: Cross-sectional study. Setting: An outpatient neurology clinic. Subjects: Eighty patients diagnosed with clinically definite multiple sclerosis. Measures: The subscales physical and mental fatigue of the Multidimensional Fatigue Inventory; the Hospital Anxiety and Depression Scale and the Cognitive Failure Questionnaire. Cognitive performance was assessed by an extensive neuropsychological test battery, including several tasks requiring effortful information processing. Results: Both anxiety and depression and mental fatigue significantly contributed to cognitive complaints, explaining respectively about 9% and 39% of the total variance. The contribution of physical fatigue to cognitive complaints was not significant. Both physical and mental fatigue did not significantly contribute to cognitive performance in terms of mental speed, attention, memory and executive functioning. Conclusions: To refine interventions for those patients with cognitive complaints, we advise adding measurements of anxiety, depression and fatigue to their neuropsychological assessment. Fatigue permits extensive neuropsychological assessment, which is needed to detect cognitive impairment in multiple sclerosis. [ABSTRACT FROM AUTHOR]

Objective To investigate the association between cognition and daily life functioning in dementia subtypes. Methods Cross-sectional data were used from 615 patients with dementia who were referred to the Maastricht Memory Clinic of the Maastricht University Medical Centre. Pearson correlation coefficients were calculated between the Mini-Mental State Examination (MMSE; to measure cognitive status) and the Blessed Dementia Scale (BDS; to measure daily life functioning) for the following types of dementia: Alzheimer's Disease (AD, n = 442); Vascular dementia (VaD, n = 113); frontotemporal dementia (FTD, n = 18); Parkinson's dementia (PD, n = 21); and primary progressive aphasia (PPA, n = 21). One-way ANOVA was used to test differences in age, MMSE scores and BDS scores across dementia subtypes. Results Scores on the MMSE showed strong correlation with BDS scores in cases of FTD (r = -0.80); moderate correlation in cases of AD, VaD, and PD (range r = -0.50–0.60); while no correlation was found in PPA cases. Conclusions The association between cognition and daily life functioning varied among dementia subtypes for AD, VaD, FTD and PD. Furthermore, the overall scores on both domains differ between dementia subtypes, indicating that different types of dementia are characterized by a specific pattern of cognitive status and daily life functioning. These findings underline the need for multidomain assessment in patients with dementia. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: The EQ-5D is a reliable tool for measuring Health-Related Quality of Life (HRQoL). However, concern has been expressed that it may ignore elements of HRQoL, particularly cognition. In response to this concern, the EQ-5D has been extended with a cognitive dimension (EQ-5D+C). The aim of this study was to compare the performance of the EQ-5D and the EQ- 5D+C in elderly patients with cognitive impairments by assessing their construct validity and responsiveness. Methods: Data from the MEDICIE study (n = 196) were used, in which all questionnaires were rated by proxies. Results: Regarding construct validity, we found similar correlations between the EQ-5D and the Mini Mental State Examination (MMSE) and between the EQ-5D+C and the MMSE. Furthermore, both the EQ-5D and the EQ-5D+C were responsive to changes in the MMSE, with the EQ-5D performing slightly better. Conclusion: We conclude that the EQ-5D performs well for evaluating HRQoL in a population with cognitive impairments. Based on the results of this explorative study, it does not seem necessary to adjust the current classification system by adding a cognitive dimension. However, in order to compare both instruments regarding utility values, it is necessary to develop a new scoring algorithm for the EQ-5D+C by conducting a general population study. Considering the explorative nature of this study, it is recommended that more aspects of the validity of both the EQ-5D and the EQ-5D+C are explored in patients with cognitive impairments using a more tailored study design. [ABSTRACT FROM AUTHOR]