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BackgroundWhite matter hyperintensities (WMH), a biomarker of small vessel disease, are often found in Alzheimer’s disease (AD) and their advanced detection and quantification can be beneficial for research and clinical applications. To investigate WMH in large-scale multicenter studies on cognitive impairment and AD, appropriate automated WMH segmentation algorithms are required. This study aimed to compare the performance of segmentation tools and provide information on their application in multicenter research.MethodsWe used a pseudo-randomly selected dataset (n = 50) from the DZNE-multicenter observational Longitudinal Cognitive Impairment and Dementia Study (DELCODE) that included 3D fluid-attenuated inversion recovery (FLAIR) images from participants across the cognitive continuum. Performances of top-rated algorithms for automated WMH segmentation [Brain Intensity Abnormality Classification Algorithm (BIANCA), lesion segmentation toolbox (LST), lesion growth algorithm (LGA), LST lesion prediction algorithm (LPA), pgs, and sysu_media] were compared to manual reference segmentation (RS).ResultsAcross tools, segmentation performance was moderate for global WMH volume and number of detected lesions. After retraining on a DELCODE subset, the deep learning algorithm sysu_media showed the highest performances with an average Dice’s coefficient of 0.702 (±0.109 SD) for volume and a mean F1-score of 0.642 (±0.109 SD) for the number of lesions. The intra-class correlation was excellent for all algorithms (>0.9) but BIANCA (0.835). Performance improved with high WMH burden and varied across brain regions.ConclusionTo conclude, the deep learning algorithm, when retrained, performed well in the multicenter context. Nevertheless, the performance was close to traditional methods. We provide methodological recommendations for future studies using automated WMH segmentation to quantify and assess WMH along the continuum of cognitive impairment and AD dementia.

Background: Non‐pharmacological interventions are a potential strategy to maintain or promote cognitive functioning in older adults. We investigated the effects of 18‐months meditation or non‐native language training versus no intervention on cognition in older adults. Method: Age‐Well was an observer‐blind, randomised, controlled clinical trial with three parallel arms. Cognitively healthy adults aged ≥ 65 years and were recruited in France. Participants were randomised (1:1:1) to a meditation training, non‐native language (English) training, or a no intervention group for 18 months. Cognition (a pre‐specified secondary outcome) was assessed pre‐ and post‐intervention via the Preclinical Alzheimer's Cognitive Composite 5 (PACC5), and composites assessing episodic memory, executive function, and attention. Linear mixed models, adjusted for age, sex, and education, evaluated cognitive changes between arms. Baseline neocortical amyloid deposition was added as a fixed effect in a sensitivity analysis. Additional sensitivity analyses assessed intervention effects for participants who attended at least 20% of intervention classes or were classified as 'responders'. Results: 137 participants were randomly assigned to meditation training (n = 45), non‐native language training (n = 46), or no intervention (n = 46). Two participants were excluded for not meeting eligibility criteria, and one died during follow‐up (Figure 1). A positive effect of non‐native language training was observed on episodic memory relative to the no intervention group (0·32 [95% CI: 0·04‐0·61], p = 0·025), and on PACC5 scores compared to meditation training (0·33 [95% CI: 0·01‐0·66], p = 0·045; Figure 2). In sensitivity analyses, neither the inclusion of amyloid as an additional covariate nor the exclusion of participants who attended <20% of intervention classes affected results. Following exclusion of 'non‐responders', evidence for beneficial effects (relative to the no intervention group) on episodic memory became significant for meditation training (0·33 [0·01, 0·66]), and was weakened for non‐native language training (0·30 [‐0·02, 0·62]). No other between‐group differences emerged. Conclusion: Among cognitively healthy older adults, there was limited evidence for positive effects of 18‐months meditation training on cognition. However, in addition to having real‐life utility, non‐native language learning in late life may have beneficial effects on cognitive domains affected early in Alzheimer's disease. Studies investigating whether these effects are long‐lasting are warranted. [ABSTRACT FROM AUTHOR]

Introduction: Older adults experiencing subjective cognitive decline (SCD) have a heightened risk of developing dementia and frequently experience subclinical anxiety, which is itself associated with dementia risk. Objective: To understand whether subclinical anxiety symptoms in SCD can be reduced through behavioral interventions. Methods: SCD-Well is a randomized controlled trial designed to determine whether an 8-week mindfulness-based intervention (caring mindfulness-based approach for seniors; CMBAS) is superior to a structurally matched health self-management program (HSMP) in reducing subclinical anxiety. Participants were recruited from memory clinics at 4 European sites. The primary outcome was change in anxiety symptoms (trait subscale of the State-Trait Anxiety Inventory; trait-STAI) from pre- to postintervention. Secondary outcomes included a change in state anxiety and depression symptoms postintervention and 6 months postrandomization (follow-up). Results: One hundred forty-seven participants (mean [SD] age: 72.7 [6.9] years; 64.6% women; CMBAS, n = 73; HSMP, n = 74) were included in the intention-to-treat analysis. There was no difference in trait-STAI between groups postintervention (adjusted change difference: –1.25 points; 95% CI –4.76 to 2.25) or at follow-up (adjusted change difference: –0.43 points; 95% CI –2.92 to 2.07). Trait-STAI decreased postintervention in both groups (CMBAS: –3.43 points; 95% CI –5.27 to –1.59; HSMP: –2.29 points; 95% CI –4.14 to –0.44) and reductions were maintained at follow-up. No between-group differences were observed for change in state anxiety or depression symptoms. Conclusions: A time-limited mindfulness intervention is not superior to health self-management in reducing subclinical anxiety symptoms in SCD. The sustained reduction observed across both groups suggests that subclinical anxiety symptoms in SCD are modifiable. ClinicalTrials.gov identifier: NCT03005652. [ABSTRACT FROM AUTHOR]

Background: The Lifetime of Experiences questionnaire (LEQ, Valenzuela and Sachdev, 2007) is an instrument that comprehensively assesses mental activity (education/occupation and leisure activities) across the lifespan (13‐30, 30‐65, 65‐present). The LEQ has been associated with brain health outcomes and cognitive decline. Challenges for the use of this questionnaire across countries include the different education systems and occupation classifications. The objectives of this study were to (1) harmonize the LEQ across Spain, United Kingdom (UK), France and Germany, (2) assess its correlation with a similar tool and (3) assess between‐country differences. Method: The LEQ was administered to 359 cognitively unimpaired older adults (age: 71.2 ± 6 years, education: 13.2 ± 3.5 years) from IMAP+ and Medit‐Ageing European projects. The original scale was translated from English to Spanish, French and German by a professional translation service and iteratively edited by native speakers. Education systems and classification of occupations were harmonized considering between‐country differences and in line with international guidelines. Scoring guidelines were adapted to allow between‐country comparison. We performed Pearson correlations with a similar instrument, the Cognitive Activities Questionnaire (CAQ, Wilson et al., 2003). Between‐country differences were assessed using ANOVA models. Result: There were no between‐country differences in participant's age and education (p>0.1). Between and within countries, the total LEQ score showed moderate to strong associations with the total CAQ score (full sample: r=0.48, Spain: r=0.74, UK: r=0.56, France: r=0.46, all p<0.001; Germany: r=0.41, p<0.05) (Figure 1). Correlation coefficients between the CAQ and LEQ were stronger within (all r>0.35) than between (all r≤0.35) periods. We observed between‐countries differences in lifespan mental activities (p=0.019, Spain > France and Germany > France), notably, during young adulthood (p=0.01, Germany > France) and late life (p=0.01, Spain > UK, Spain > France) (Figure 2). These differences were explained by leisure activities engagement rather than by differences in education and occupation (p<0.001, Young adulthood and Midlife: Spain > UK & France, Germany > France; Late life: Spain > UK & France & Germany) (Figure 3). Conclusion: The harmonized LEQ allowed comparison of complex mental activities ‐ including education and occupation ‐ across countries and was related to another questionnaire measuring mental activity across the lifespan. [ABSTRACT FROM AUTHOR]

Background: As part of the updated NIA‐AA Research Framework for Alzheimer's disease (AD), a numeric clinical staging scheme, applicable only to individuals in the Alzheimer's continuum, has been introduced. "Stage 2" is defined as a transitional stage, characterized by subtle or subjective decline in cognition or neuropsychiatric symptoms (NPS) that might reflect underlying AD pathology (Jack et al., Alzheimers Dement. 2018). Here, we aimed to cluster a sample of cognitively healthy participants based on stage 2 criteria and compare the emerging clusters with regard to differences in CSF biomarker status. Method: For this analysis, we included baseline data of N = 349 cognitively healthy participants with available CSF biomarker information from the DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study. A two‐step cluster analysis (TSCA) was applied based on CSF Aß42/40 status and stage 2 criteria, which included a) subtle objective cognitive impairment (<0.5SD) in any of five factor scores from DELCODE's neuropsychological test battery, b) subjective cognitive decline (SCD) with concern in any of the five SCD‐Interview domains and c) the presence of agitation, depression, anxiety, disinhibition, irritability or sleep disturbances on the Neuropsychiatric Inventory Questionnaire [NPI‐Q]. The TSCA identifies the optimal number of clusters by grouping cases into preclusters first and then clustering those using a hierarchical algorithm. Result: The TSCA yielded three clusters. Cluster 1 (n = 114) was characterized by subtle cognitive impairment in memory, language, executive function and working memory as well as SCD in the memory and language domain. In contrast, cluster 2 (n = 104) was predominantly formed by participants that reported SCD and NPS without subtle objective impairment. In cluster 3 (n = 121), none of the stage 2 criteria were prominent. In comparison to clusters 2 and 3, participants in cluster 1 had lower levels of Aß42/40 (H(2) = 11.58, p =.003) and Aß42/ptau‐181 (H(2) = 12.06, p =.002). We observed no significant differences between clusters 2 and 3. Conclusion: Our analysis resulted in three distinct clusters of cognitively healthy participants with different distributions of stage 2 criteria. The criteria prominent in participants of cluster 1 seem most promising to identify individuals at risk of progression due to underlying AD pathology. [ABSTRACT FROM AUTHOR]

Background: The latest NIA‐AA Research Framework for Alzheimer's disease (AD) includes a numerical staging system for individuals in the Alzheimer's continuum. The authors introduce "stage 2" as a transitional stage, characterized by the earliest detectable cognitive or neurobehavioral changes. We aimed to characterize stage 2 in a large German multicentre cohort study. Method: Our analysis included baseline data of N = 349 cognitively healthy participants with available CSF biomarker information from the DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study. A subsample of n = 110 participants presented with abnormal Aß42/40 biomarkers and was therefore classified as part of the Alzheimer's continuum. Stage 2 characteristics at baseline were defined by subjective decline with concern in any domain on the SCD interview that persisted for at least 6 months. In addition, subtle impairment of objective cognitive performance (<0,5SD) was derived from factor scores of the DELCODE neuropsychological test battery. Subtle neurobehavioral changes were defined by the presence of at least one neuropsychiatric symptom (NPS) on the Neuropsychiatric Inventory Questionnaire (NPI‐Q). Result: The majority of participants in the Alzheimer's continuum presented with only SCD (22.7%) or both SCD and NPS (20.9%), whereas 12.7% presented with only NPS and 5.5% with only subtle objective cognitive decline. While 10.9% showed all three stage 2 characteristics, 14.5% showed none. The distribution of stage 2 characteristics differed between participants in the Alzheimer's continuum and those with normal Aß42/40 (X2(7)=21.21, p<.01). In addition, the number of fulfilled stage 2 criteria was higher in participants with abnormal Aß42/40 (M=1.41, SD=0.87) compared to those with normal amyloid biomarkers (M=1.10, SD=0.84, t(347)=1.45, p=.001). Conclusion: Our findings provide a systematic overview on stage 2 characteristics in a large cohort of cognitively healthy participants with abnormal AD biomarkers and indicate that both the number of fulfilled stage 2 criteria and their distribution differs from participants outside the Alzheimer's continuum. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive decline (SCD) denotes self‐reported cognitive concerns in the absence of objective cognitive impairment. Individuals with SCD convert to dementia at twice the annual rate of healthy controls, with relatively poorer cognition in SCD conferring additional risk. Non‐pharmacological interventions are currently undergoing intensive evaluation for promoting cognitive function in SCD. Method: This study utilized data from the SCD‐Well randomized controlled trial. One hundred forty‐seven older adults with SCD, recruited from clinics in four European countries, were randomized to one of two 8‐week non‐pharmacological interventions: the Caring Mindfulness‐Based Approach for Seniors (CMBAS), or a Health Self‐Management Program (HSMP). Participants' objective cognitive performance was assessed at baseline, post‐intervention, and 24‐weeks follow‐up using a battery of tests. Four of these (RAVLT, WAIS‐IV Coding, Mattis DRS‐2 and Category Fluency) were combined to yield an abridged version of the Preclinical Alzheimer's Cognitive Composite 5 (PACC5Abridged). Linear mixed models estimated the change in outcome measures (the PACC5Abridged and its constituents) within and between arms. All models were adjusted for country and participant demographics (sex, age, and education), as well as the time‐varying effect of participants' repeated practice with the outcome measures. Result: There was a statistically significant improvement in the PACC5Abridged in both arms of the trial (p<.001), which did not differ between groups. The mean change in PACC5Abridged from baseline to 24‐weeks was 0.28 for CMBAS, and 0.22 for HSMP (pooled baseline SD 0.72). The effect of participants' repeated practice on the PACC5Abridged was non‐significant, ruling out retest effects as a substantive explanation for results. Amongst the PACC5Abridged constituent tests, significant improvement was observed in the RAVLT and WAIS‐IV Coding. Conclusion: This clinical trial evaluated the effect of two 8‐week non‐pharmacological interventions on objective cognitive performance in SCD. Scores on a composite measure of early Alzheimer's disease related cognitive dysfunction improved in both arms, even after accounting for practice effects. These results paralleled those of the primary outcome measure (trait anxiety), for which scores also improved in both arms. This work adds to the growing body of evidence that non‐pharmacological interventions can impact cognition in individuals at increased risk of dementia. [ABSTRACT FROM AUTHOR]

Background: Subjectively experienced cognitive decline (SCD), particularly associated with worries, in older adults is known to be a risk factor for dementia. So far, only few studies focus on gender‐specific profiles in SCD. Method: Gender differences in SCD subjects who were enrolled in the SCD‐Well trial were analyzed with regard to their perception of subjective cognitive difficulties and the corresponding objective cognitive performance. SCD‐Well is a multicenter, observer‐blinded, randomized, and controlled superiority trial (Marchant et al. 2018). Two different types of 8‐week interventions are compared within the study: a mindfulness‐ and compassion‐based intervention with a validated health education program. 147 participants (95 female) were included. Data from the SCD‐Interview (SCD‐I; Miebach et al., 2019), the Cognitive Difficulties Scale (CDS; McNair & Kahn, 1983), and different cognitive scales summarized in a modified Preclinical Alzheimer's Cognitive Composite (PACC; Donohue et al., 2014) were analyzed for gender differences. Result: Statistical analyses revealed no gender differences concerning variables of the SCD‐I and CDS. Regarding objective cognitive performance, a significant gender effect for the PACC score with men showing lower cognitive performance was detected (U = 1859.00 , p <.05). However, only women showed a negative correlation between the PACC and reported SCD as indicated on the SCD‐I (r=‐.436, p= <.001) and CDS (r = ‐.514, p <.001): more subjective cognitive difficulties and worries were associated with lower cognitive performance. To further explore this relationship, we will analyse differences between sites. Conclusion: Literature reveals gender differences in SCD for objective cognition, neuroimaging and biomarkers (Wang & Tian, 2018). The present study supports the finding of woman performing better in a cognitive assessment than men. Moreover, it adds to this literature by showing an association between self‐perceived cognitive difficulties and actual cognitive performance in women, but not men. Further research is needed to provide a deeper understanding of gender differences in SCD, which are highly relevant for approaches on early detection of cognitive decline, which might in turn impact the choice of pre‐clinical interventions. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive decline (SCD) without objective performance deficits reflects in some individuals the earliest symptomatic manifestation of Alzheimer's Disease (AD) at the late preclinical stage1,2. It is crucial to delineate the relationship between SCD, AD‐specific biomarkers and the localization of early neurodegeneration. Method: We included the baseline‐dataset of the DELCODE‐study3 (n=943), from which 404 subjects (57 AD, 89 mild cognitive impairment (MCI), 171 SCD, and 87 healthy controls (CO)) received both CSF‐biomarker‐assessment (Aβ‐42, total‐tau, phosphorylated‐tau) and structural MRI. Cortical thickness was estimated with the FreeSurfer‐Software‐package version 6.0. ANCOVAs with one between‐subject factor of diagnosis, and age, sex, and scanner‐sites as covariates were calculated for the bilateral entorhinal cortices (EC) and bilateral parahippocampi (PH), respectively. Two‐way ANCOVAs with between‐subject factors of diagnosis (SCD/CO) and CSF‐biomarkers (positive/negative) and the same covariates were calculated for each of the regions of interests (ROIs) and CSF‐biomarkers. Result: Significant main effects for diagnosis were found for the one‐way‐ANCOVAs for all ROIs (p<0.001; bilateral EC and left PH: HC=SCD>MCI>AD; right PH: HC>SCD>MCI>AD). Two way‐ANCOVA showed significant main effects for diagnosis for the bilateral PH‐thickness (left: p=0.031; right: p=0.013), and an interaction between diagnosis and CSF‐Aß42 for the left PH‐thickness (p=0.022). Post‐hoc analyses showed the interactions were driven by decreased bilateral PH and left EC thickness in SCD subjects compared to CO in the Aβ42 positive subgroups only (p<0.05), not between the Aß42 negative subgroups. Two‐way‐ANCOVA showed also significant interaction effects between the diagnosis and total‐tau, and between the diagnosis and phosphorylated‐tau in the right EC (t‐tau: p=0.011; p‐tau: p=0.004), where SCD subjects had lower right entorhinal thickness than controls in the tau positive subgroups. Conclusion: We found decreased bilateral parahippocampal and left entorhinal thickness in persons with SCD compared to controls in all amyloid‐positive cases. In addition, the right entorhinal cortex seems to be affected in SCD compared to controls in all tau positive cases. These data suggest that, in addition to positive AD pathology indicated by CSF biomarkers, the first clinical symptoms such as cognitive complaints may also indicate early degenerative processes in the course of the disease. [ABSTRACT FROM AUTHOR]

Background: The primary focus of mindfulness‐based program (MBP) research to date has been on mental health. More recently, attention has turned to putative effects on cognition. An evidence synthesis is required to answer the key question of 'Do MBPs confer cognitive benefit, and if so, for whom?' A particularly crucial distinction is whether benefits differ according to individuals' age. We undertook a systematic review and meta‐analysis of all relevant research across the adult lifespan. Method: This review was conducted according to PRISMA guidelines, registered on Prospero (#CRD42018100904), and conducted searches of 7 databases. Included studies must have used a group‐based MBP, randomized participants to conditions, and used objective cognitive outcome measures. Two independent researchers assessed studies against criteria, extracted data and rated study quality. Meta‐analyses used robust variance estimation to assess overall effects. Result: Forty‐six studies were included in the systematic review, and 38 contributed effect sizes for meta‐analysis (see figure). Across the studies included in the meta‐analysis, the cognitive domains most frequently assayed were executive function (66 outcomes) and attention (60 outcomes). All outcome measures were pooled for analysis. The studies of working‐age adults (18‐65 years old; k=28) included healthy, psychiatric and neurological samples (k=16 passively controlled studies; k=12 actively controlled studies). Studies of older adults (>65 years old; k=10) included healthy persons, and patients with subjective and objective cognitive impairment (k=7 passively controlled studies; k=3 actively controlled studies). When combining healthy and clinical studies of working‐age adults, meta‐analysis yielded a non‐significant pooled effect of MBP participation on cognitive performance compared to control conditions (g=0.28, p=.14; see table). A significant pooled effect was observed for the studies featuring older adults (g=0.27, p<.05; see table). Conclusion: The current review assessed the effects of MBPs relative to control conditions on cognitive performance in adults across the lifespan, and found evidence of a significant positive effect for older adults only. No evidence of a benefit for younger populations was identified. As research in this fast‐developing field continues, it will be possible to examine whether effects vary according to healthy or clinical status, and to establish whether specific cognitive domains are differentially impacted. [ABSTRACT FROM AUTHOR]