A Web-Based Intervention Based on Acceptance and Commitment Therapy for Family Caregivers of People With Dementia: Mixed Methods Feasibility Study.

BACKGROUND: Acceptance and commitment therapy (ACT), as an empirically based third-wave cognitive behavioral therapy, has shown promise in enhancing well-being and functioning across diverse populations. However, in the context of caregiving, the effect size of available ACT interventions remains at best moderate, sometimes accompanied by high dropout rates, highlighting the need for more effective and feasible intervention designs. OBJECTIVE: The objective of our study was to evaluate the feasibility and acceptability of a fully online ACT program designed for family caregivers of people with dementia. This study aimed to boost psychological flexibility and support caregivers, enabling them to realize and prioritize their own life values alongside their caregiving responsibilities. METHODS: A mixed methods feasibility study using an uncontrolled pretest-posttest design was conducted. This intervention included a 9-week web-based self-help program based on ACT incorporating collaborative goal setting and weekly web-based motivational coaching for family caregivers of people with dementia. This study involved 30 informal caregivers recruited through memory clinics and social media platforms in the Netherlands and received approval from the Medical Ethics Committee of the Maastricht University Medical Center+ (NL77389.068.21/metc21-029). RESULTS: A total of 24 caregivers completed the postintervention assessment, indicating a high adherence rate (24/29, 83%). Caregivers reported positive feedback regarding collaborative goal setting, but some found challenges in implementing new skills due to their own habitual responses or the unpredictable context of dementia caregiving. Personalizing the intervention based on individual value preferences was highlighted as beneficial. CONCLUSIONS: Compared to other web-based self-help ACT interventions for family caregivers, this intervention showed a high adherence and sufficient level of feasibility, which underscores the use of personalization in delivering web-based interventions. Moreover, the potential of this ACT-based intervention for family caregivers of people with dementia was demonstrated, suggesting that further research and a larger-scale controlled trial are warranted to validate its effectiveness. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2022-070499.

Relation of the kynurenine pathway with normal age: A systematic review.

BACKGROUND: The kynurenine pathway (KP) is gaining more attention as a common pathway involved in age-related conditions. However, which changes in the KP occur due to normal ageing is still largely unclear. The aim of this systematic review was to summarize the available evidence for associations of KP metabolites with age. METHODS: We used an broad search strategy and included studies up to October 2023. RESULTS: Out of 8795 hits, 55 studies were eligible for the systematic review. These studies suggest that blood levels of tryptophan decrease with age, while blood and cerebrospinal fluid levels of kynurenine and its ratio with tryptophan increase. Studies investigating associations between cerebrospinal fluid and blood levels of kynurenic acid and quinolinic acid with age reported either positive or non-significant findings. However, there is a large heterogeneity across studies. Additionally, most studies were cross-sectional, and only few studies investigated associations with other downstream kynurenines. CONCLUSIONS: This systematic review suggests that levels of kynurenines are positively associated with age. Larger and prospective studies are needed that also investigate a more comprehensive panel of KP metabolites and changes during the life-course.

The role of the kynurenine pathway in cognitive functioning after stroke: A prospective clinical study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (ß 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 (pinteraction = .008; ß per SD 0.15 [95% CI 0.02, 0.27]). These associations did not change over time. CONCLUSIONS: 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.

White Matter Hyperintensity Volume and Poststroke Cognition: An Individual Patient Data Pooled Analysis of 9 Ischemic Stroke Cohort Studies.

BACKGROUND: White matter hyperintensities (WMH) are associated with cognitive dysfunction after ischemic stroke. Yet, uncertainty remains about affected domains, the role of other preexisting brain injury, and infarct types in the relation between WMH burden and poststroke cognition. We aimed to disentangle these factors in a large sample of patients with ischemic stroke from different cohorts. METHODS: We pooled and harmonized individual patient data (n=1568) from 9 cohorts, through the Meta VCI Map consortium (www.metavcimap.org). Included cohorts comprised patients with available magnetic resonance imaging and multidomain cognitive assessment <15 months poststroke. In this individual patient data meta-analysis, linear mixed models were used to determine the association between WMH volume and domain-specific cognitive functioning (Z scores; attention and executive functioning, processing speed, language and verbal memory) for the total sample and stratified by infarct type. Preexisting brain injury was accounted for in the multivariable models and all analyses were corrected for the study site as a random effect. RESULTS: In the total sample (67 years [SD, 11.5], 40% female), we found a dose-dependent inverse relationship between WMH volume and poststroke cognitive functioning across all 4 cognitive domains (coefficients ranging from -0.09 [SE, 0.04, P=0.01] for verbal memory to -0.19 [SE, 0.03, P<0.001] for attention and executive functioning). This relation was independent of acute infarct volume and the presence of lacunes and old infarcts. In stratified analyses, the relation between WMH volume and domain-specific functioning was also largely independent of infarct type. CONCLUSIONS: In patients with ischemic stroke, increasing WMH volume is independently associated with worse cognitive functioning across all major domains, regardless of old ischemic lesions and infarct type.

The use of Acceptance and Commitment Therapy (ACT) in informal caregivers of people with dementia and other long-term or chronic conditions: A systematic review and conceptual integration.

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.

Sex Differences in Poststroke Cognitive Impairment: A Multicenter Study in 2343 Patients With Acute Ischemic Stroke.

BACKGROUND: Poststroke cognitive impairment (PSCI) occurs in about half of stroke survivors. Cumulative evidence indicates that functional outcomes of stroke are worse in women than men. Yet it is unknown whether the occurrence and characteristics of PSCI differ between men and women. METHODS: Individual patient data from 9 cohorts of patients with ischemic stroke were harmonized and pooled through the Meta-VCI-Map consortium (n=2343, 38% women). We included patients with visible symptomatic infarcts on computed tomography/magnetic resonance imaging and cognitive assessment within 15 months after stroke. PSCI was defined as impairment in ≥1 cognitive domains on neuropsychological assessment. Logistic regression analyses were performed to compare men to women, adjusted for study cohort, to obtain odds ratios for PSCI and individual cognitive domains. We also explored sensitivity and specificity of cognitive screening tools for detecting PSCI, according to sex (Mini-Mental State Examination, 4 cohorts, n=1814; Montreal Cognitive Assessment, 3 cohorts, n=278). RESULTS: PSCI was found in 51% of both women and men. Men had a lower risk of impairment of attention and executive functioning (men: odds ratio, 0.76 [95% CI, 0.61-0.96]), and language (men: odds ratio, 0.67 [95% CI, 0.45-0.85]), but a higher risk of verbal memory impairment (men: odds ratio, 1.43 [95% CI, 1.17-1.75]). The sensitivity of Mini-Mental State Examination (<25) for PSCI was higher for women (0.53) than for men (0.27; P=0.02), with a lower specificity for women (0.80) than men (0.96; P=0.01). Sensitivity and specificity of Montreal Cognitive Assessment (<26.) for PSCI was comparable between women and men (0.91 versus 0.86; P=0.62 and 0.29 versus 0.28; P=0.86, respectively). CONCLUSIONS: Sex was not associated with PSCI occurrence but affected domains differed between men and women. The latter may explain why sensitivity of the Mini-Mental State Examination for detecting PSCI was higher in women with a lower specificity compared with men. These sex differences need to be considered when screening for and diagnosing PSCI in clinical practice.

Tear biomarkers for Alzheimer's disease screening and diagnosis (the TearAD study): design and rationale of an observational longitudinal multicenter study.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia, and due to increasing life expectancy the number of patients is expected to grow. The diagnosis of AD involves the use of biomarkers determined by an amyloid PET scan or cerebrospinal fluid analyses that are either invasive or expensive, and not available in each hospital, thus limiting their usage as a front-line screener. The TearAD study aims to use tear fluid as a potential source for AD biomarkers. In previous reports, we demonstrated that AD biomarkers amyloid-beta and tau, are measurable in tear fluid and are associated with disease severity and neurodegeration. This study aims to validate previous results in a larger cohort and evaluate the diagnostic accuracy of tear biomarkers to discriminate between individuals with and without neurodegeneration as determined by hippocampal atrophy. METHODS: The TearAD study is an observational longitudinal multi-center study that will enroll 50 cognitively healthy controls, 50 patients with subjective cognitive decline, 50 patients with mild cognitive impairment and 50 patients with AD dementia from the memory clinic. Participants will be examined at baseline, after one year, and after two years follow-up. Study assessments include neuropsychological tests and ophthalmic examination. All participants will receive a MRI scan, and a subset of the study population will undergo cerebral spinal fluid collection and an amyloid PET scan. Tear fluid will be collected with Schirmer strips and levels of Aß38, Aß40, Aß42, t-tau and p-tau in tear fluid will be determined using multiplex immunoassays. Blood samples will be collected from all participants. Images of the retina will be obtained with a standard, hyperspectral and ultra-wide field fundus camera. Additionally, macular pigment optical density will be measured with the macular pigment reflectometer, and cross-sectional images of the retina will be obtained through optical coherence tomography imaging. DISCUSSION: The TearAD study will provide insight into the potential diagnostic use of tear biomarkers as a minimally invasive and low cost tool for the screening and diagnosis of AD. TRIAL REGISTRATION: Retrospectively registered at clinicaltrials.gov (NCT05655793).

Determinants of quality of life in family caregivers in MCI: a comparison with mild dementia.

OBJECTIVES: The aim of the current study was to investigate the health-related quality of life (HRQol) of the family caregiver in MCI, explore possible determinants and study possible differences with mild dementia. METHODS: This secondary data analysis included 145 persons with MCI and 154 persons with dementia and their family caregivers from two Dutch cohort studies. HRQoL was measured with the VAS of the EuroQol-5D-3L version. Regressions analyses were conducted to examine potential demographic and clinical determinants of the caregiver's HRQoL. RESULTS: The mean EQ5D-VAS in family caregivers of persons with MCI was 81.1 (SD 15.7), and did not significantly differ from family caregivers in mild dementia (81.9 (SD 13.0)). In MCI, patient measurements were not significantly associated with caregiver mean EQ5D-VAS. Concerning caregiver characteristics, being a spouse and a lower educational level were associated with a lower mean EQ5D-VAS (in a multiple linear regression model: unstandardized B -8.075, p = 0.013 and unstandardized B -6.162, p = 0.037 resp.). In mild dementia, the NPI item irritability showed an association with caregiver EQ5D-VAS in bivariate linear regression analyses. CONCLUSION: Results indicate that especially family caregiver characteristics seem to influence family caregiver HRQoL in MCI. Future research should include other potential determinants such as burden, coping strategies and relationship quality.

Correlations between kynurenines in plasma and CSF, and their relation to markers of Alzheimer's disease pathology.

INTRODUCTION: 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 (Aß1-42) and tau levels in patients from the memory clinic spanning the whole cognitive spectrum. METHODS: 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 Aß1-42, 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. RESULTS: 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 Aß1-42, t-tau or p-tau. Plasma levels of KA/QA were negatively correlated with Aß1-42 (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 Aß1-42. 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). CONCLUSIONS: 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.

Anxiety and cognitive functioning in the Maastricht study: A cross-sectional population study.

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.

Association Between Cognition, Health Related Quality of Life, and Costs in a Population at Risk for Cognitive Decline.

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.

The cardiometabolic depression subtype and its association with clinical characteristics: The Maastricht Study.

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.

Distinct Patterns Link the BDNF Val66Met Polymorphism to Alzheimer's Disease Pathology.

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-ß (Aß)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-Aß42 in APOE ɛ4+ carriers, independent of p-tau, while Val-Val displayed greater p-tau at higher IL-6 and sub-threshold Aß42. This may contribute to resolving some inconsistencies in the BDNF literature and provide possible inroads to specific Aß and tau interventions depending on BDNF polymorphism.

Network impact score is an independent predictor of post-stroke cognitive impairment: A multicenter cohort study in 2341 patients with acute ischemic stroke.

BACKGROUND: Post-stroke cognitive impairment (PSCI) is a common consequence of stroke. Accurate prediction of PSCI risk is challenging. The recently developed network impact score, which integrates information on infarct location and size with brain network topology, may improve PSCI risk prediction. AIMS: To determine if the network impact score is an independent predictor of PSCI, and of cognitive recovery or decline. METHODS: We pooled data from patients with acute ischemic stroke from 12 cohorts through the Meta VCI Map consortium. PSCI was defined as impairment in ≥ 1 cognitive domain on neuropsychological examination, or abnormal Montreal Cognitive Assessment. Cognitive recovery was defined as conversion from PSCI < 3 months post-stroke to no PSCI at follow-up, and cognitive decline as conversion from no PSCI to PSCI. The network impact score was related to serial measures of PSCI using Generalized Estimating Equations (GEE) models, and to PSCI stratified according to post-stroke interval (<3, 3-12, 12-24, >24 months) and cognitive recovery or decline using logistic regression. Models were adjusted for age, sex, education, prior stroke, infarct volume, and study site. RESULTS: We included 2341 patients with 4657 cognitive assessments. PSCI was present in 398/844 patients (47%) <3 months, 709/1640 (43%) at 3-12 months, 243/853 (28%) at 12-24 months, and 208/522 (40%) >24 months. Cognitive recovery occurred in 64/181 (35%) patients and cognitive decline in 26/287 (9%). The network impact score predicted PSCI in the univariable (OR 1.50, 95%CI 1.34-1.68) and multivariable (OR 1.27, 95%CI 1.10-1.46) GEE model, with similar ORs in the logistic regression models for specified post-stroke intervals. The network impact score was not associated with cognitive recovery or decline. CONCLUSIONS: The network impact score is an independent predictor of PSCI. As such, the network impact score may contribute to a more precise and individualized cognitive prognostication in patients with ischemic stroke. Future studies should address if multimodal prediction models, combining the network impact score with demographics, clinical characteristics and other advanced brain imaging biomarkers, will provide accurate individualized prediction of PSCI. A tool for calculating the network impact score is freely available at https://metavcimap.org/features/software-tools/lsm-viewer/.

A comparison of two approaches for modeling dementia progression in a changing patient context.

OBJECTIVES: To explain the heterogeneity in dementia disease trajectory, we studied the influence of changing patient characteristics on disease course by comparing the association of dementia progression with baseline comorbidity and frailty, and with time-varying comorbidity and frailty. METHODS: We used individual growth models to study baseline and time-varying associations in newly diagnosed dementia patients (n = 331) followed for 3 years. We measured cognition using the Mini-Mental State Examination (MMSE), daily functioning using the Disability Assessment for Dementia (DAD), frailty using the Fried criteria and comorbidity using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). RESULTS: Although baseline comorbidity and frailty were associated with decreased daily functioning at diagnosis, their effects clearly diminished over time. In contrast, when incorporating comorbidity and frailty as time-varying covariates, comorbidity was associated with lower daily functioning, and frailty with both lower cognition and daily functioning. Being frail was associated with a 0.9-point lower MMSE score (p = 0.03) and a 14.9-point lower DAD score (p < 0.01). A 1-point increase in CIRS-G score was associated with a 1.1-point lower DAD score (p < 0.01). CONCLUSIONS: Time-varying comorbidity and frailty were more consistently associated with dementia disease course than baseline comorbidity and frailty. Therefore, modeling only baseline predictors is insufficient for understanding the course of dementia in a changing patient context.

The Role of Vascular Risk Factors in Biomarker-Based AT(N) Groups: A German-Dutch Memory Clinic Study.

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 Aß42 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.

Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer's disease.

BACKGROUND: Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer's disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels. METHODS: We performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer's Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study. RESULTS: We found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood-brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC, associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins. CONCLUSIONS: CSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood-brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles.

Worry Modifies the Relationship between Locus Coeruleus Activity and Emotional Mnemonic Discrimination.

BACKGROUND: The locus coeruleus (LC) plays a critical role in modulating emotional memory performance via widespread connections to the medial temporal lobe (MTL). Interestingly, both the LC and MTL are affected during aging. Therefore, we aimed to investigate whether worry during cognitive aging changes the relationship between memory performance and the neural activity patterns during an emotional memory task. METHODS: Twenty-eight participants aged 60-83 years from the Maastricht Aging study conducted an emotional mnemonic discrimination task during a 7T fMRI-scan. We performed a robust multiple linear regression to examine the association between worry and mnemonic memory performance under different levels of arousal. Subsequently, we examined if worry modifies the relationship between neuronal activity and mnemonic memory performance. RESULTS: We observed that under low arousal, only participants with low compared to high levels of worry benefitted from additional LC activity. Under high arousal, additional LC activity was associated with lower mnemonic memory performance. CONCLUSION: Our results suggest there might be an optimal involvement of the NA-system for optimal memory discrimination performance, as we observed that under low levels of worry and with lower levels of arousal, higher LC activity might be needed to achieve similar levels of optimal memory performance as achieved under higher arousal when LC activity remained lower.