User Experience of a (Semi-) Automated Cognitive Phone-Based Assessment Within a Memory Clinic Population.

OBJECTIVE: We examined the user experience in different modalities (face-to-face, semi-automated phone-based, and fully automated phone-based) of cognitive testing in people with subjective cognitive decline and mild cognitive impairment. METHOD: A total of 67 participants from the memory clinic of the Maastricht University Medical Center+ participated in the study. The study consisted of cognitive tests in different modalities, namely, face-to-face, semi-automated phone-based guided by a researcher, and fully automated phone-based without the involvement of a researcher. After each assessment, a user experience questionnaire was administered, including questions about, for example, satisfaction, simplicity, and missing personal contact, on a seven-point Likert scale. Non-parametric tests were used to compare user experiences across different modalities. RESULTS: In all modalities, user experiences were rated above average. The face-to-face ratings were comparable to the ratings of the semi-automated phone-based assessment, except for the satisfaction and recommendation items, which were rated higher for the face-to-face assessment. The face-to-face assessment was preferred above the fully automated phone-based assessment on all items. In general, the semi- and fully automated phone-based assessments were comparable (simplicity, conceivability, quality of sound, visiting the hospital, and missing personal contact), while on all the other items, the semi-automated phone-based assessment was preferred. CONCLUSIONS: User experience was rated high within all modalities. Simplicity, conceivability, comfortability, and participation scores were comparable in the semi-automated phone-based and face-to-face assessment. Based on these findings and earlier research on validation of the semi-automated phone-based assessment, the semi-automated assessment could be useful for screening for clinical trials, and after more research, in clinical practice.

Synaptic protein CSF levels relate to memory scores in individuals without dementia.

INTRODUCTION: We investigated how cerebrospinal fluid levels of synaptic proteins associate with memory function in normal cognition (CN) and mild cognitive impairment (MCI), and investigated the effect of amyloid positivity on these associations. METHODS: We included 242 CN (105(43%) abnormal amyloid), and 278 MCI individuals (183(66%) abnormal amyloid) from EMIF-AD MBD and ADNI. For 181 (EMIF-AD MBD) and 36 (ADNI) proteins with a synaptic annotation in SynGO, associations with word learning recall were analysed with linear models. RESULTS: Subsets of synaptic proteins showed lower levels with worse recall in preclinical AD (EMIF-AD MBD: 7, ADNI: 5 proteins, none overlapping), prodromal AD (EMIF-AD MBD only, 27 proteins) and non-AD MCI (EMIF-AD MBD: 1, ADNI: 7 proteins). The majority of these associations were specific to these groups. DISCUSSION: Synaptic disturbance-related memory impairment occurred very early in AD, indicating it may be relevant to develop therapies targeting the synapse early in the disease.

Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study.

INTRODUCTION: We investigated blood DNA methylation patterns associated with 15 well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration. METHODS: We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF-AD) study using the EPIC array. RESULTS: We identified Bonferroni-significant differential methylation associated with CSF YKL-40 (five loci) and neurofilament light chain (NfL; seven loci) levels, with two of the loci associated with CSF YKL-40 levels correlating with plasma YKL-40 levels. A co-localization analysis showed shared genetic variants underlying YKL-40 DNA methylation and CSF protein levels, with evidence that DNA methylation mediates the association between genotype and protein levels. Weighted gene correlation network analysis identified two modules of co-methylated loci correlated with several amyloid measures and enriched in pathways associated with lipoproteins and development. DISCUSSION: We conducted the most comprehensive epigenome-wide association study (EWAS) of AD-relevant CSF biomarkers to date. Future work should explore the relationship between YKL-40 genotype, DNA methylation, and protein levels in the brain. HIGHLIGHTS: Blood DNA methylation was assessed in the EMIF-AD MBD study. Epigenome-wide association studies (EWASs) were performed for 15 Alzheimer's disease (AD)-relevant cerebrospinal fluid (CSF) biomarker measures. Five Bonferroni-significant loci were associated with YKL-40 levels and seven with neurofilament light chain (NfL). DNA methylation in YKL-40 co-localized with previously reported genetic variation. DNA methylation potentially mediates the effect of single-nucleotide polymorphisms (SNPs) in YKL-40 on CSF protein levels.

Blood-based multivariate methylation risk score for cognitive impairment and dementia.

INTRODUCTION: The established link between DNA methylation and pathophysiology of dementia, along with its potential role as a molecular mediator of lifestyle and environmental influences, positions blood-derived DNA methylation as a promising tool for early dementia risk detection. METHODS: In conjunction with an extensive array of machine learning techniques, we employed whole blood genome-wide DNA methylation data as a surrogate for 14 modifiable and non-modifiable factors in the assessment of dementia risk in independent dementia cohorts. RESULTS: We established a multivariate methylation risk score (MMRS) for identifying mild cognitive impairment cross-sectionally, independent of age and sex (P = 2.0 × 10-3). This score significantly predicted the prospective development of cognitive impairments in independent studies of Alzheimer's disease (hazard ratio for Rey's Auditory Verbal Learning Test (RAVLT)-Learning = 2.47) and Parkinson's disease (hazard ratio for MCI/dementia = 2.59). DISCUSSION: Our work shows the potential of employing blood-derived DNA methylation data in the assessment of dementia risk. HIGHLIGHTS: We used whole blood DNA methylation as a surrogate for 14 dementia risk factors. Created a multivariate methylation risk score for predicting cognitive impairment. Emphasized the role of machine learning and omics data in predicting dementia. The score predicts cognitive impairment development at the population level.

Involvement of the choroid plexus in Alzheimer's disease pathophysiology: findings from mouse and human proteomic studies.

BACKGROUND: Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer's disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relation between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans. METHODS: We used an APP knock-in mouse model, APPNL-G-F, exhibiting amyloid pathology, to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF using liquid chromatography mass spectrometry. Mouse proteomes were investigated at the age of 7 weeks (n = 5) and 40 weeks (n = 5). Results were compared with previously published human AD CSF proteomic data (n = 496) to identify key proteins and pathways associated with ChP changes in AD. RESULTS: ChP tissue proteome was dysregulated in APPNL-G-F mice relative to wild-type mice at both 7 and 40 weeks. At both ages, ChP tissue proteomic changes were associated with epithelial cells, mitochondria, protein modification, extracellular matrix and lipids. Nonetheless, some ChP tissue proteomic changes were different across the disease trajectory; pathways related to lysosomal function, endocytosis, protein formation, actin and complement were uniquely dysregulated at 7 weeks, while pathways associated with nervous system, immune system, protein degradation and vascular system were uniquely dysregulated at 40 weeks. CSF proteomics in both mice and humans showed similar ChP-related dysregulated pathways. CONCLUSIONS: Together, our findings support the hypothesis of ChP dysfunction in AD. These ChP changes were related to amyloid pathology. Therefore, the ChP could become a novel promising therapeutic target for AD.

Facing the Next "Geriatric Giant"-A Systematic Literature Review and Meta-Analysis of Interventions Tackling Loneliness and Social Isolation Among Older Adults.

OBJECTIVES: Loneliness and social isolation are associated with adverse health outcomes, especially within the older adult population, underlining the need for effective interventions. This systematic review and meta-analysis aims to summarize all available evidence regarding the effectiveness of interventions for loneliness and social isolation, to map out their working mechanisms, and to give implications for policy and practice. DESIGN: Systematic literature review and meta-analysis. SETTING AND PARTICIPANTS: Older adults (≥65 years). METHODS: A systematic search was conducted in MEDLINE, PsycINFO, and CINAHL for studies quantitively or qualitatively assessing effects of interventions for loneliness and social isolation in older adults, following predefined selection criteria. Risk of bias as well as small study effects were assessed and, wherever appropriate, information about effect sizes of individual studies pooled using random-effects meta-analyses. Sources for between-study heterogeneity were explored using meta-regression. RESULTS: Of n = 2223 identified articles, n = 67 were eventually included for narrative synthesis. Significant intervention effects were reported for a proportion of studies (55.9% and 50.0% for loneliness and social isolation, respectively) and 57.6% of studies including a follow-up measure (n = 29) reported sustained intervention effects. Meta-analysis of n = 27 studies, representing n = 1756 participants, suggested a medium overall effect of loneliness interventions (d = -0.47; 95% CI, -0.62 to -0.32). Between-study heterogeneity was substantial and could not be explained by differences in study design, year of publication, outcome measures, intervention length, participant demographics, setting, baseline level of loneliness, or geographic location. However, non-technology-based interventions reported larger effect sizes on average (Δd = -0.35; 95% CI, -0.66 to -0.04; P = .029) and were more often significant. Qualitative assessment of potential intervention mechanisms resulted in 3 clusters of effective components: "promoting social contact," "transferring knowledge and skills," and "addressing social cognition". CONCLUSIONS AND IMPLICATIONS: Interventions for loneliness and social isolation can generally be effective, although some unexplained between-study heterogeneity remains. Further research is needed regarding the applicability of interventions across different settings and countries, also considering their cost-effectiveness.

Moving forward with dementia: an explorative cross-country qualitative study into post-diagnostic experiences.

OBJECTIVES: This explorative cross-country qualitative study aims to describe experiences of receiving a dementia diagnosis and experiences of support following a diagnosis in Australia, Canada, the Netherlands and Poland. METHOD: Qualitative study using projective techniques during online focus groups, online and telephone interviews with people with dementia and caregivers. RESULTS: Twenty-three people with dementia and 53 caregivers participated. Qualitative content analysis revealed five themes; (1) 'Coming to terms with dementia' helped people deal with complex emotions to move forward. (3) 'The social network as a source of support' and (4) 'The challenges and realities of formal support' and impacted 'Coming to terms with dementia'. (2) 'Navigating life with dementia as a caregiver' highlights caregiver burden and was impacted by (4) 'The challenges and realities of formal support'. People were (5) 'Self-caring and preparing for tomorrow' as they focused on maintaining current health whilst planning the future. Despite differences in healthcare and post-diagnostic support systems, there were more similarities across countries than differences. CONCLUSION: Across countries, formal support and support from friends and family are crucial for people with dementia and caregivers to come to terms with dementia and maintain carer wellbeing to ultimately live well with dementia.

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.

A proof of concept phase II study with the PDE-4 inhibitor roflumilast in patients with mild cognitive impairment or mild Alzheimer's disease dementia (ROMEMA): study protocol of a double-blind, randomized, placebo-controlled, between-subjects trial.

BACKGROUND: Research into the neurobiological underpinnings of learning and memory has demonstrated the cognitive-enhancing effects associated with diverse classes of phosphodiesterase (PDE) inhibitors. Specific PDE inhibitors have been identified to improve neuronal communication through selective inhibition of PDE activity. Roflumilast, a PDE4 inhibitor, has demonstrated efficacy in enhancing episodic memory in healthy adults and elderly participants with pronounced memory impairment, indicative of amnestic mild cognitive impairment (aMCI). In alignment with these findings, the present protocol aims to provide a proof of concept phase II of the potential of roflumilast to aid patients diagnosed with (a)MCI or mild Alzheimer's disease (AD) dementia. METHODS: The study will be conducted according to a double-blind, randomized placebo-controlled, between-subjects design. Participants with (a)MCI and mild AD dementia will be recruited through the Memory Clinic at the Maastricht University Medical Centre + (MUMC +) in Maastricht, the Netherlands, alongside outreach through regional hospitals, and social media. The study will have three arms: placebo, 50 µg roflumilast, and 100 µg roflumilast, with a treatment duration of 24 weeks. The primary outcome measure will focus on the assessment of episodic memory, as evaluated through participants' performance on the 15-word Verbal Learning Task (VLT). Our secondary objectives are multifaceted, including an exploration of various cognitive domains. In addition, insights into the well-being and daily functioning of participants will be investigated through interviews with both the participants and their (informal) caregivers, we are interested in the well-being and daily functioning of the participants. DISCUSSION: The outcomes of the present study aim to elucidate the significance of the PDE4 inhibition mechanism as a prospective therapeutic target for enhancing cognitive function in individuals with (a)MCI and mild AD dementia. Identifying positive effects within these patient cohorts could extend the relevance of this treatment to encompass a broader spectrum of neurological disorders. TRIAL REGISTRATION: The Medical Ethics Committee of MUMC + granted ethics approval for the 4th version of the protocol on September 10th, 2020. The trial was registered at the European Drug Regulatory Affairs Clinical Trials (EudraCT) registered on the 19th of December 2019 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004959-36/NL ) and ClinicalTrial.gov (NCT04658654, https://clinicaltrials.gov/study/NCT04658654?intr=roflumilast&cond=mci&rank=1 ) on the 8th of December 2020. The Central Committee on Research Involving Human Subjects (CCMO) granted approval on the 30th of September 2020.

Needs for Care, Service Use and Quality of Life in Dementia: 12-Month Follow-Up of the Actifcare Study in Portugal.

INTRODUCTION: The intermediate stages of dementia are relatively under-researched, including in Portugal. The Actifcare (ACcess to TImely Formal Care) EU-JPND project studied people with mild-moderate dementia, namely their needs, access to and use of community services (e.g., day centers, home support). In our baseline assessment of the Portuguese Actifcare cohort, the unmet needs of some participants would call for formal support, which was not always accessible or used. We now report the main results of the 12-month follow-up, analyzing changes in needs, service (non)use, quality of life and related variables. METHODS: This was a longitudinal, observational study using a convenience sample of 54 dyads of people with dementia and their family carers. Our main outcomes were the Camberwell Assessment of Need for the Elderly (CANE) and the Resources Utilization in Dementia. Clinical-functional, quality of life, psychological distress and caregiving-related assessments were also used. RESULTS: At follow-up, the cognitive and functional status of people with dementia declined (p < 0.001), and their neuropsychiatric symptoms increased (p = 0.033). Considering CANE interviewers' ratings, the total needs of people with dementia increased at follow-up (p < 0.001) but not the unmet needs. Quality of life was overall stable. The use of formal care did not increase significantly, but informal care did in some domains. Carers' depressive symptoms increased (p = 0.030) and perseverance time decreased (p = 0.045). However, carers' psychological distress unmet needs were lower (p = 0.007), and their stress and quality of life remained stable. CONCLUSION: People with dementia displayed complex biopsychosocial unmet needs. Their cognitive-functional decline over one year was not accompanied by a corresponding increase in any pattern of unmet need, nor of service use. Reliance on informal care (namely supervision) may have contributed to this. Caregiving-related outcomes evolved according to different trends, although stability was almost the rule. Primary carers were even more present at follow-up, without an apparently heavier toll on their own needs, burden, and quality of life. Overall, this longitudinal study comprehensively assessed Portuguese community-dwelling people with dementia. Despite the lack of generalizability, participants' needs remained overall stable and partly unmet over one year. Longer follow-up periods are needed to understand such complex processes.

European intersocietal recommendations for the biomarker-based diagnosis of neurocognitive disorders.

The recent commercialisation of the first disease-modifying drugs for Alzheimer's disease emphasises the need for consensus recommendations on the rational use of biomarkers to diagnose people with suspected neurocognitive disorders in memory clinics. Most available recommendations and guidelines are either disease-centred or biomarker-centred. A European multidisciplinary taskforce consisting of 22 experts from 11 European scientific societies set out to define the first patient-centred diagnostic workflow that aims to prioritise testing for available biomarkers in individuals attending memory clinics. After an extensive literature review, we used a Delphi consensus procedure to identify 11 clinical syndromes, based on clinical history and examination, neuropsychology, blood tests, structural imaging, and, in some cases, EEG. We recommend first-line and, if needed, second-line testing for biomarkers according to the patient's clinical profile and the results of previous biomarker findings. This diagnostic workflow will promote consistency in the diagnosis of neurocognitive disorders across European countries.

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 Reliability and Clinical Validation of Automatically-Derived Verbal Memory Features of the Verbal Learning Test in Early Diagnostics of Cognitive Impairment.

BACKGROUND: Previous research has shown that verbal memory accurately measures cognitive decline in the early phases of neurocognitive impairment. Automatic speech recognition from the verbal learning task (VLT) can potentially be used to differentiate between people with and without cognitive impairment. OBJECTIVE: Investigate whether automatic speech recognition (ASR) of the VLT is reliable and able to differentiate between subjective cognitive decline (SCD) and mild cognitive impairment (MCI). METHODS: The VLT was recorded and processed via a mobile application. Following, verbal memory features were automatically extracted. The diagnostic performance of the automatically derived features was investigated by training machine learning classifiers to distinguish between participants with SCD versus MCI/dementia. RESULTS: The ICC for inter-rater reliability between the clinical and automatically derived features was 0.87 for the total immediate recall and 0.94 for the delayed recall. The full model including the total immediate recall, delayed recall, recognition count, and the novel verbal memory features had an AUC of 0.79 for distinguishing between participants with SCD versus MCI/dementia. The ten best differentiating VLT features correlated low to moderate with other cognitive tests such as logical memory tasks, semantic verbal fluency, and executive functioning. CONCLUSIONS: The VLT with automatically derived verbal memory features showed in general high agreement with the clinical scoring and distinguished well between SCD and MCI/dementia participants. This might be of added value in screening for cognitive impairment.

The quality of family relationships in dementia: Mixed methods to unravel mixed feelings.

Objective: Close relationships influence health and quality of life outcomes for people with dementia and their families. Yet, we know little on the role of different relationship domains with quantitative methods having proved to have limitations in this research field. We aimed to study these relationship domains over time, contrasting the views of people with dementia and their family carers, making use of both quantitative and qualitative approaches.Methods: A convergent mixed methods design was adopted, analysing longitudinal data (four time points over three years) from 66 dyads of Portuguese community-dwelling people with dementia and their primary carers, from the EU-Actifcare project sample. Quantitative assessments used sociodemographic and clinical variables, and Positive Affect Index scores, with descriptive and inferential analyses. Qualitative data, collected through individual and joint semi-structured interviews, were explored using thematic analysis.Results: Both quantitative and qualitative findings demonstrated that some domains of relationship quality are affected in different ways, with changes occurring at different stages. Some (e.g., 'communication') may even improve after initial decline. 'Closeness' was consistently altered over time, from carers' perspectives, and played an important protective role regarding institutionalisation. Overall, changes in the relationship quality were perceived differently by people with dementia and their carers, and these divergent perspectives often led to tension. Qualitative data revealed that 'mixed feelings' (ambivalence) involve complex experiences, arguably more difficult to manage than negative feelings alone. Furthermore, perceived informal support, particularly from the extended family, and receiving formal services' assistance, seemed to facilitate positive (re)appraisals of the relationship.Conclusions: A deeper understanding of relationship quality and its domains as dementia progresses may help tailoring interventions to tackle modifiable aspects of relationships, meeting the needs and cherishing the resources of dyads and families. Timely assessments could identify relationships at risk and need for support, including for alternative caring arrangements.

Contributions of Vascular Burden and Amyloid Abnormality to Cognitive Decline in Memory Clinic Patients.

Background: Alzheimer's disease pathology and vascular burden are highly prevalent and often co-occur in elderly. It remains unclear how both relate to cognitive decline. Objective: To investigate whether amyloid abnormality and vascular burden synergistically contribute to cognitive decline in a memory clinic population. Methods: We included 227 patients from Maastricht and Aachen memory clinics. Amyloid abnormality (A+) was defined by CSF Aß42 using data-driven cut-offs. Vascular burden (V+) was defined as having moderate to severe white matter hyperintensities, or any microbleeds, macrohemorrhage or infarcts on MRI. Longitudinal change in global cognition, memory, processing speed, executive functioning, and verbal fluency was analysed across the A-V-, A-V+, A+V-, A+V+ groups by linear mixed models. Additionally, individual MRI measures, vascular risk and vascular disease were used as V definitions. Results: At baseline, the A+V+ group scored worse on global cognition and verbal fluency compared to all other groups, and showed worse memory compared to A-V+ and A-V- groups. Over time (mean 2.7+ - 1.5 years), A+V+ and A+V- groups showed faster global cognition decline than A-V+ and A-V- groups. Only the A+V- group showed decline on memory and verbal fluency. The A-V+ group did not differ from the A-V- group. Individual MRI vascular measures only indicated an independent association of microbleeds with executive functioning decline. Findings were similar using other V definitions. Conclusions: Our study demonstrates that amyloid abnormality predicts cognitive decline independent from vascular burden in a memory clinic population. Vascular burden shows a minor contribution to cognitive decline in these patients. This has important prognostic implications.

Validation of an Automated Speech Analysis of Cognitive Tasks within a Semiautomated Phone Assessment.

Introduction: We studied the accuracy of the automatic speech recognition (ASR) software by comparing ASR scores with manual scores from a verbal learning test (VLT) and a semantic verbal fluency (SVF) task in a semiautomated phone assessment in a memory clinic population. Furthermore, we examined the differentiating value of these tests between participants with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). We also investigated whether the automatically calculated speech and linguistic features had an additional value compared to the commonly used total scores in a semiautomated phone assessment. Methods: We included 94 participants from the memory clinic of the Maastricht University Medical Center+ (SCD N = 56 and MCI N = 38). The test leader guided the participant through a semiautomated phone assessment. The VLT and SVF were audio recorded and processed via a mobile application. The recall count and speech and linguistic features were automatically extracted. The diagnostic groups were classified by training machine learning classifiers to differentiate SCD and MCI participants. Results: The intraclass correlation for inter-rater reliability between the manual and the ASR total word count was 0.89 (95% CI 0.09-0.97) for the VLT immediate recall, 0.94 (95% CI 0.68-0.98) for the VLT delayed recall, and 0.93 (95% CI 0.56-0.97) for the SVF. The full model including the total word count and speech and linguistic features had an area under the curve of 0.81 and 0.77 for the VLT immediate and delayed recall, respectively, and 0.61 for the SVF. Conclusion: There was a high agreement between the ASR and manual scores, keeping the broad confidence intervals in mind. The phone-based VLT was able to differentiate between SCD and MCI and can have opportunities for clinical trial screening.

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 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.

Socioeconomic position, modifiable dementia risk and cognitive decline: results of 12-year Maastricht Aging Study.

OBJECTIVES: This study investigated whether the association between modifiable dementia risk and rate of cognitive decline differs across socioeconomic status (SES) strata. DESIGN, SETTING AND PARTICIPANTS: Data were used from Maastricht Aging Study, a prospective cohort study with a 12-year follow-up. The baseline sample consisted of 1023 adults over 40 years old. MEASUREMENTS: The "LIfestyle for BRAin health" (LIBRA) index was used to assess modifiable dementia risk. Cognitive performance was assessed at baseline, 6 and 12 years, and measured in the domains of information processing speed, executive functioning and verbal memory function. An SES score was calculated from equivalent income and educational level (tertiles). Linear mixed models were used to study the association between LIBRA, SES and their interaction on the rate of cognitive decline. RESULTS: Participants in the lowest SES tertile displayed more decline in information processing speed (vs. middle SES: X2 = 7.08, P = 0.029; vs. high SES: X2 = 9.49, P = 0.009) and verbal memory (vs. middle SES: X2 = 9.28, P < 0.001; vs. high SES: X2 = 16.68, P < 0.001) over 6 years compared to their middle- and high-SES counterparts. Higher (unhealthier) LIBRA scores were associated with more decline in information processing speed (X2 = 12.66, P = 0.002) over 12 years and verbal memory (X2 = 4.63, P = 0.032) over 6 years. No consistent effect modification by SES on the association between LIBRA and cognition was found. CONCLUSIONS: Results suggest that lifestyle is an important determinant of cognitive decline across SES groups. Yet, people with low SES had a more unfavorable modifiable risk score suggesting more potential for lifestyle-based interventions.

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.