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Abstract Background Blood-brain barrier (BBB) alterations may contribute to AD pathology through various mechanisms, including impaired amyloid-β (Aβ) clearance and neuroinflammation. Soluble platelet-derived growth factor receptor beta (sPDGFRβ) has emerged as a potential biomarker for BBB integrity. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) offers a direct assessment of BBB permeability. However, the relationship between BBB dysfunction, cognitive impairment, and AD pathology remains unclear, with inconsistent findings in the literature. Methods We conducted a cross-sectional study using data from the DELCODE and DESCRIBE cohorts to investigate BBB dysfunction in participants with normal cognition (NC), mild cognitive impairment (MCI), and AD dementia. BBB function was assessed using DCE-MRI and sPDGFRβ levels in cerebrospinal fluid and AD biomarkers Aβ and tau were measured. In a subset of patients, the CSF/plasma-ratio of albumin (QAlb) as a standard marker of BBB integrity and markers of neuroinflammation were analyzed. Results 91 participants (NC: 44, MCI: 21, AD: 26) were included in the analysis. The average age was 74.4 years, 42% were female. Increased hippocampal BBB disruption was observed in the AD-group (Ktrans: 0.55 × 10− 3 min− 1 ± 0.74 × 10− 3 min− 1) but not the MCI-group (Ktrans: 0.177 × 10− 3 min− 1 ± 0.22 × 10− 3 min− 1), compared to the NC group (Ktrans: 0.19 × 10− 3 min− 1 ± 0.37 × 10− 3 min− 1, p

Abstract Synucleinopathies such as Parkinson’s disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.

Global socio-environmental challenges and local impacts, global agendas, and local implementation: multi-level governance has never been more important – or more complex. To keep track of progress and the challenges in sustainable urban development, monitoring systems at all levels are at different stages of development and in need of harmonisation. In this context, national reporting can link the global level with the local one by identifying and reviewing framework conditions, and setting indicator and data standards for cities, counties, and municipalities. This raises questions about the awareness of different issues, resource imbalances and, not least, the effectiveness of standardised monitoring. This paper provides valuable insights into the lessons learned from the preparation of the first national progress report on the implementation of the New Urban Agenda. The reflections could support further governance and monitoring efforts not only at the national level but also across all levels.

Abstract INTRODUCTION Soluble amyloid beta (Aβ) oligomers have been suggested as initiating Aβ related neuropathologic change in Alzheimer's disease (AD) but their quantitative distribution and chronological sequence within the AD continuum remain unclear. METHODS A total of 526 participants in early clinical stages of AD and controls from a longitudinal cohort were neurobiologically classified for amyloid and tau pathology applying the AT(N) system. Aβ and tau oligomers in the quantified cerebrospinal fluid (CSF) were measured using surface‐based fluorescence intensity distribution analysis (sFIDA) technology. RESULTS Across groups, highest Aβ oligomer levels were found in A+ with subjective cognitive decline and mild cognitive impairment. Aβ oligomers were significantly higher in A+T− compared to A−T− and A+T+. APOE ε4 allele carriers showed significantly higher Aβ oligomer levels. No differences in tau oligomers were detected. DISCUSSION The accumulation of Aβ oligomers in the CSF peaks early within the AD continuum, preceding tau pathology. Disease‐modifying treatments targeting Aβ oligomers might have the highest therapeutic effect in these disease stages. Highlights Using surface‐based fluorescence intensity distribution analysis (sFIDA) technology, we quantified Aβ oligomers in cerebrospinal fluid (CSF) samples of the DZNE‐Longitudinal Cognitive Impairment and Dementia (DELCODE) cohort Aβ oligomers were significantly elevated in mild cognitive impairment (MCI) Amyloid‐positive subjects in the subjective cognitive decline (SCD) group increased compared to the amyloid‐negative control group Interestingly, levels of Aβ oligomers decrease at advanced stages of the disease (A+T+), which might be explained by altered clearing mechanisms

Abstract Background Age-associated deterioration of the immune system contributes to a chronic low-grade inflammatory state known as “inflammaging” and is implicated in the pathogenesis of late-onset Alzheimer's disease (LOAD). Whether changes in the tissue environment caused by circulatory factors associated with aging may alter the innate immune response is unknown. Monocyte-derived macrophages (Mo-MФs) infiltrating the brain alongside microglia are postulated to play a modulatory role in LOAD and both express triggering receptor expressed on myeloid cells 2 (TREM2). Apolipoprotein E (APOE) acts as a ligand for TREM2, and their role in amyloid beta (Aβ) clearance highlights their importance in LOAD. However, the influence of the patient's own milieu (autologous serum) on the synthesis of TREM2 and APOE in infiltrating macrophages remains unknown. Objectives To functionally assess patient-specific TREM2 and APOE synthesis, we designed a personalized assay based on Mo-MФs using monocytes from LOAD patients and matched controls (CO). We assessed the influence of each participant’s own milieu, by examining the effect of short- (1 day) and long- (10 days) term differentiation of the cells in the presence of the donor´s autologous serum (AS) into M1-, M2- or M0-macrophages. Additionally, sex differences and Aβ-uptake ability in short- and long-term differentiated Mo-MФs were assessed. Results We showed a time-dependent increase in TREM2 and APOE protein levels in LOAD- and CO-derived cells. While AS did not differentially modulate TREM2 compared to standard fetal calf serum (FCS), AS decreased APOE levels in M2 macrophages but increased levels in M1 macrophages. Interestingly, higher levels of TREM2 and lower levels of APOE were detected in female- than in male- LOAD patients. Finally, we report decreased Aβ-uptake in long-term differentiated CO- and LOAD-derived cells, particularly in APOEε4(+) carriers. Conclusions We demonstrate for the first time the suitability of a personalized Mo-MФ cell culture-based assay for studying functional TREM2 and APOE synthesis in a patient's own aged milieu. Our strategy may thus provide a useful tool for future research on diagnostic and therapeutic aspects of personalized medicine.

BackgroundParticipation in multimodal leisure activities, such as playing a musical instrument, may be protective against brain aging and dementia in older adults (OA). Potential neuroprotective correlates underlying musical activity remain unclear.ObjectiveThis cross-sectional study investigated the association between lifetime musical activity and resting-state functional connectivity (RSFC) in three higher-order brain networks: the Default Mode, Fronto-Parietal, and Salience networks.MethodsWe assessed 130 cognitively unimpaired participants (≥ 60 years) from the baseline cohort of the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Lifetime musical activity was operationalized by the self-reported participation in musical instrument playing across early, middle, and late life stages using the Lifetime of Experiences Questionnaire (LEQ). Participants who reported musical activity during all life stages (n = 65) were compared to controls who were matched on demographic and reserve characteristics (including education, intelligence, socioeconomic status, self-reported physical activity, age, and sex) and never played a musical instrument (n = 65) in local (seed-to-voxel) and global (within-network and between-network) RSFC patterns using pre-specified network seeds.ResultsOlder participants with lifetime musical activity showed significantly higher local RSFC between the medial prefrontal cortex (Default Mode Network seed) and temporal as well as frontal regions, namely the right temporal pole and the right precentral gyrus extending into the superior frontal gyrus, compared to matched controls. There were no significant group differences in global RSFC within or between the three networks.ConclusionWe show that playing a musical instrument during life relates to higher RSFC of the medial prefrontal cortex with distant brain regions involved in higher-order cognitive and motor processes. Preserved or enhanced functional connectivity could potentially contribute to better brain health and resilience in OA with a history in musical activity.Trial registrationGerman Clinical Trials Register (DRKS00007966, 04/05/2015).

Abstract INTRODUCTION We investigated the association of inflammatory mechanisms with markers of Alzheimer's disease (AD) pathology and rates of cognitive decline in the AD spectrum. METHODS We studied 296 cases from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study (DELCODE) cohort, and an extension cohort of 276 cases of the Alzheimer's Disease Neuroimaging Initiative study. Using Bayesian confirmatory factor analysis, we constructed latent factors for synaptic integrity, microglia, cerebrovascular endothelial function, cytokine/chemokine, and complement components of the inflammatory response using a set of inflammatory markers in cerebrospinal fluid. RESULTS We found strong evidence for an association of synaptic integrity, microglia response, and cerebrovascular endothelial function with a latent factor of AD pathology and with rates of cognitive decline. We found evidence against an association of complement and cytokine/chemokine factors with AD pathology and rates of cognitive decline. DISCUSSION Latent factors provided access to directly unobservable components of the neuroinflammatory response and their association with AD pathology and cognitive decline.

Abstract Background Alzheimer’s disease (AD) is characterized by the intra- and extracellular accumulation of amyloid-β (Aβ) peptides. How Aβ aggregates perturb the proteome in brains of patients and AD transgenic mouse models, remains largely unclear. State-of-the-art mass spectrometry (MS) methods can comprehensively detect proteomic alterations, providing relevant insights unobtainable with transcriptomics investigations. Analyses of the relationship between progressive Aβ aggregation and protein abundance changes in brains of 5xFAD transgenic mice have not been reported previously. Methods We quantified progressive Aβ aggregation in hippocampus and cortex of 5xFAD mice and controls with immunohistochemistry and membrane filter assays. Protein changes in different mouse tissues were analyzed by MS-based proteomics using label-free quantification; resulting MS data were processed using an established pipeline. Results were contrasted with existing proteomic data sets from postmortem AD patient brains. Finally, abundance changes in the candidate marker Arl8b were validated in cerebrospinal fluid (CSF) from AD patients and controls using ELISAs. Results Experiments revealed faster accumulation of Aβ42 peptides in hippocampus than in cortex of 5xFAD mice, with more protein abundance changes in hippocampus, indicating that Aβ42 aggregate deposition is associated with brain region-specific proteome perturbations. Generating time-resolved data sets, we defined Aβ aggregate-correlated and anticorrelated proteome changes, a fraction of which was conserved in postmortem AD patient brain tissue, suggesting that proteome changes in 5xFAD mice mimic disease-relevant changes in human AD. We detected a positive correlation between Aβ42 aggregate deposition in the hippocampus of 5xFAD mice and the abundance of the lysosome-associated small GTPase Arl8b, which accumulated together with axonal lysosomal membranes in close proximity of extracellular Aβ plaques in 5xFAD brains. Abnormal aggregation of Arl8b was observed in human AD brain tissue. Arl8b protein levels were significantly increased in CSF of AD patients. Conclusions We report a comprehensive biochemical and proteomic investigation of hippocampal and cortical brain tissue derived from 5xFAD transgenic mice, providing a valuable resource to the neuroscientific community. We identified Arl8b, with significant abundance changes in 5xFAD and AD patient brains. Arl8b might enable the measurement of progressive lysosome accumulation in AD patients and have clinical utility as a candidate biomarker.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, affecting a growing number of elderly people. In order to improve the early and differential diagnosis of AD, better biomarkers are needed. Glycosylation is a protein post-translational modification that is modulated in the course of many diseases, including neurodegeneration. Aiming to improve AD diagnosis and differential diagnosis through glycan analytics methods, we report the glycoprotein glycome of cerebrospinal fluid (CSF) isolated from a total study cohort of 262 subjects. The study cohort consisted of patients with AD, healthy controls and patients suffering from other types of dementia. CSF free-glycans were also isolated and analyzed in this study, and the results reported for the first time the presence of 19 free glycans in this body fluid. The free-glycans consisted of complete or truncated N-/O-glycans as well as free monosaccharides. The free-glycans Hex1 and HexNAc1Hex1Neu5Ac1 were able to discriminate AD from controls and from patients suffering from other types of dementia. Regarding CSF N-glycosylation, high proportions of high-mannose, biantennary bisecting core-fucosylated N-glycans were found, whereby only about 20% of the N-glycans were sialylated. O-Glycans and free-glycan fragments were less sialylated in AD patients than in controls. To conclude, this comprehensive study revealed for the first time the biomarker potential of free glycans for the differential diagnosis of AD.

Inferior frontal sulcal hyperintensities (IFSHs) on fluid-attenuated inversion recovery (FLAIR) sequences have been proposed to be indicative of glymphatic dysfunction. Replication studies in large and diverse samples are nonetheless needed to confirm them as an imaging biomarker. We investigated whether IFSHs were tied to Alzheimer’s disease (AD) pathology and cognitive performance. We used data from 361 participants along the AD continuum, who were enrolled in the multicentre DELCODE study. The IFSHs were rated visually based on FLAIR magnetic resonance imaging. We performed ordinal regression to examine the relationship between the IFSHs and cerebrospinal fluid-derived amyloid positivity and tau positivity (Aβ42/40 ratio ≤ 0.08; pTau181 ≥ 73.65 pg/mL) and linear regression to examine the relationship between cognitive performance (i.e., Mini-Mental State Examination and global cognitive and domain-specific performance) and the IFSHs. We controlled the models for age, sex, years of education, and history of hypertension. The IFSH scores were higher in those participants with amyloid positivity (OR: 1.95, 95% CI: 1.05–3.59) but not tau positivity (OR: 1.12, 95% CI: 0.57–2.18). The IFSH scores were higher in older participants (OR: 1.05, 95% CI: 1.00–1.10) and lower in males compared to females (OR: 0.44, 95% CI: 0.26–0.76). We did not find sufficient evidence linking the IFSH scores with cognitive performance after correcting for demographics and AD biomarker positivity. IFSHs may reflect the aberrant accumulation of amyloid β beyond age.

Abstract Background White matter hyperintensities (WMH) in subjects across the Alzheimer’s disease (AD) spectrum with minimal vascular pathology suggests that amyloid pathology—not just arterial hypertension—impacts WMH, which in turn adversely influences cognition. Here we seek to determine the effect of both hypertension and Aβ positivity on WMH, and their impact on cognition. Methods We analysed data from subjects with a low vascular profile and normal cognition (NC), subjective cognitive decline (SCD), and amnestic mild cognitive impairment (MCI) enrolled in the ongoing observational multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study (n = 375, median age 70.0 [IQR 66.0, 74.4] years; 178 female; NC/SCD/MCI 127/162/86). All subjects underwent a rich neuropsychological assessment. We focused on baseline memory and executive function—derived from multiple neuropsychological tests using confirmatory factor analysis—, baseline preclinical Alzheimer’s cognitive composite 5 (PACC5) scores, and changes in PACC5 scores over the course of three years (ΔPACC5). Results Subjects with hypertension or Aβ positivity presented the largest WMH volumes (p FDR

Abstract Background The NIA-AA proposed amyloid-tau-neurodegeneration (ATN) as a classification system for AD biomarkers. The amyloid cascade hypothesis (ACH) implies a sequence across ATN groups that patients might undergo during transition from healthy towards AD: A−T−N−➔A+T−N−➔A+T+N−➔A+T+N+. Here we assess the evidence for monotonic brain volume decline for this particular (amyloid-conversion first, tau-conversion second, N-conversion last) and alternative progressions using voxel-based morphometry (VBM) in a large cross-sectional MRI cohort. Methods We used baseline data of the DELCODE cohort of 437 subjects (127 controls, 168 SCD, 87 MCI, 55 AD patients) which underwent lumbar puncture, MRI scanning, and neuropsychological assessment. ATN classification was performed using CSF-Aβ42/Aβ40 (A+/−), CSF phospho-tau (T+/−), and adjusted hippocampal volume or CSF total-tau (N+/−). We compared voxel-wise model evidence for monotonic decline of gray matter volume across various sequences over ATN groups using the Bayesian Information Criterion (including also ROIs of Braak stages). First, face validity of the ACH transition sequence A−T−N−➔A+T−N−➔A+T+N−➔A+T+N+ was compared against biologically less plausible (permuted) sequences among AD continuum ATN groups. Second, we evaluated evidence for 6 monotonic brain volume progressions from A−T−N− towards A+T+N+ including also non-AD continuum ATN groups. Results The ACH-based progression A−T−N−➔A+T−N−➔A+T+N−➔A+T+N+ was consistent with cognitive decline and clinical diagnosis. Using hippocampal volume for operationalization of neurodegeneration (N), ACH was most evident in 9% of gray matter predominantly in the medial temporal lobe. Many cortical regions suggested alternative non-monotonic volume progressions over ACH progression groups, which is compatible with an early amyloid-related tissue expansion or sampling effects, e.g., due to brain reserve. Volume decline in 65% of gray matter was consistent with a progression where A status converts before T or N status (i.e., ACH/ANT) when compared to alternative sequences (TAN/TNA/NAT/NTA). Brain regions earlier affected by tau tangle deposition (Braak stage I-IV, MTL, limbic system) present stronger evidence for volume decline than late Braak stage ROIs (V/VI, cortical regions). Similar findings were observed when using CSF total-tau for N instead. Conclusion Using the ATN classification system, early amyloid status conversion (before tau and neurodegeneration) is associated with brain volume loss observed during AD progression. The ATN system and the ACH are compatible with monotonic progression of MTL atrophy. Trial registration DRKS00007966, 04/05/2015, retrospectively registered.

Abstract Background In preclinical Alzheimer’s disease, it is unclear why some individuals with amyloid pathologic change are asymptomatic (stage 1), whereas others experience subjective cognitive decline (SCD, stage 2). Here, we examined the association of stage 1 vs. stage 2 with structural brain reserve in memory-related brain regions. Methods We tested whether the volumes of hippocampal subfields and parahippocampal regions were larger in individuals at stage 1 compared to asymptomatic amyloid-negative older adults (healthy controls, HCs). We also tested whether individuals with stage 2 would show the opposite pattern, namely smaller brain volumes than in amyloid-negative individuals with SCD. Participants with cerebrospinal fluid (CSF) biomarker data and bilateral volumetric MRI data from the observational, multi-centric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study were included. The sample comprised 95 amyloid-negative and 26 amyloid-positive asymptomatic participants as well as 104 amyloid-negative and 47 amyloid-positive individuals with SCD. Volumes were based on high-resolution T2-weighted images and automatic segmentation with manual correction according to a recently established high-resolution segmentation protocol. Results In asymptomatic individuals, brain volumes of hippocampal subfields and of the parahippocampal cortex were numerically larger in stage 1 compared to HCs, whereas the opposite was the case in individuals with SCD. MANOVAs with volumes as dependent data and age, sex, years of education, and DELCODE site as covariates showed a significant interaction between diagnosis (asymptomatic versus SCD) and amyloid status (Aß42/40 negative versus positive) for hippocampal subfields. Post hoc paired comparisons taking into account the same covariates showed that dentate gyrus and CA1 volumes in SCD were significantly smaller in amyloid-positive than negative individuals. In contrast, CA1 volumes were significantly (p = 0.014) larger in stage 1 compared with HCs. Conclusions These data indicate that HCs and stages 1 and 2 do not correspond to linear brain volume reduction. Instead, stage 1 is associated with larger than expected volumes of hippocampal subfields in the face of amyloid pathology. This indicates a brain reserve mechanism in stage 1 that enables individuals with amyloid pathologic change to be cognitively normal and asymptomatic without subjective cognitive decline.

Abstract Background Neuroinflammation constitutes a pathological hallmark of Alzheimer’s disease (AD). Still, it remains unresolved if peripheral inflammatory markers can be utilized for research purposes similar to blood-based beta-amyloid and neurodegeneration measures. We investigated experimental inflammation markers in serum and analyzed interrelations towards AD pathology features in a cohort with a focus on at-risk stages of AD. Methods Data of 74 healthy controls (HC), 99 subjective cognitive decline (SCD), 75 mild cognitive impairment (MCI), 23 AD relatives, and 38 AD subjects were obtained from the DELCODE cohort. A panel of 20 serum biomarkers was determined using immunoassays. Analyses were adjusted for age, sex, APOE status, and body mass index and included correlations between serum and CSF marker levels and AD biomarker levels. Group-wise comparisons were based on screening diagnosis and routine AD biomarker-based schematics. Structural imaging data were combined into composite scores representing Braak stage regions and related to serum biomarker levels. The Preclinical Alzheimer’s Cognitive Composite (PACC5) score was used to test for associations between the biomarkers and cognitive performance. Results Each experimental marker displayed an individual profile of interrelations to AD biomarkers, imaging, or cognition features. Serum-soluble AXL (sAXL), IL-6, and YKL-40 showed the most striking associations. Soluble AXL was significantly elevated in AD subjects with pathological CSF beta-amyloid/tau profile and negatively related to structural imaging and cognitive function. Serum IL-6 was negatively correlated to structural measures of Braak regions, without associations to corresponding IL-6 CSF levels or other AD features. Serum YKL-40 correlated most consistently to CSF AD biomarker profiles and showed the strongest negative relations to structure, but none to cognitive outcomes. Conclusions Serum sAXL, IL-6, and YKL-40 relate to different AD features, including the degree of neuropathology and cognitive functioning. This may suggest that peripheral blood signatures correspond to specific stages of the disease. As serum markers did not reflect the corresponding CSF protein levels, our data highlight the need to interpret serum inflammatory markers depending on the respective protein’s specific biology and cellular origin. These marker-specific differences will have to be considered to further define and interpret blood-based inflammatory profiles for AD research.

BackgroundSustained environmental enrichment (EE) through a variety of leisure activities may decrease the risk of developing Alzheimer’s disease. This cross-sectional cohort study investigated the association between long-term EE in young adulthood through middle life and microstructure of fiber tracts associated with the memory system in older adults.MethodsN = 201 cognitively unimpaired participants (≥ 60 years of age) from the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) baseline cohort were included. Two groups of participants with higher (n = 104) or lower (n = 97) long-term EE were identified, using the self-reported frequency of diverse physical, intellectual, and social leisure activities between the ages 13 to 65. White matter (WM) microstructure was measured by fractional anisotropy (FA) and mean diffusivity (MD) in the fornix, uncinate fasciculus, and parahippocampal cingulum using diffusion tensor imaging. Long-term EE groups (lower/higher) were compared with adjustment for potential confounders, such as education, crystallized intelligence, and socio-economic status.ResultsReported participation in higher long-term EE was associated with greater fornix microstructure, as indicated by higher FA (standardized β = 0.117, p = 0.033) and lower MD (β = −0.147, p = 0.015). Greater fornix microstructure was indirectly associated (FA: unstandardized B = 0.619, p = 0.038; MD: B = −0.035, p = 0.026) with better memory function through higher long-term EE. No significant effects were found for the other WM tracts.ConclusionOur findings suggest that sustained participation in a greater variety of leisure activities relates to preserved WM microstructure in the memory system in older adults. This could be facilitated by the multimodal stimulation associated with the engagement in a physically, intellectually, and socially enriched lifestyle. Longitudinal studies will be needed to support this assumption.

Local governments are highly relevant for the just-starting socio-ecological transformation. Living up to this role requires new or adapted forms of governance. The German case provides a vivid example of how the UN Sustainable Development Goals (SDGs) provide a useful framework for this transformation. In our policy-oriented contribution, we focus on the question whether the SDGs themselves are innovation drivers in local sustainability governance. We motivate this idea with the theoretical framework of public sector innovation and provide comprehensive examples of the most prevalent current approaches to SDG-related innovations at the German local government level, covering local government sustainability reporting, strategies, budgets, and financing. Our central finding is that a small group of early-innovating German local governments has already begun to govern sustainability with the help of SDG-driven innovations and that this became possible because of publicly funded support projects and accessible pre-defined localised SDGs.

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: One of the most widely used instruments for assessing agitation in dementia patients is the Cohen-Mansfield Agitation Inventory (CMAI), nevertheless no global score has been proposed. The aim of this study is: (a) to conduct a confirmatory (CFA) and exploratory factor analysis (EFA) of CMAI on people with dementia and Psychological and Behavioral Symptoms (BPSD), and (b) to propose an alternative structure, based on clinical criteria including all CMAI items. Methods: Confirmatory and exploratory factor analyses were carried out on the CMAI 29 items administered at baseline to 505 patients with dementia (PwD) and BPSD enrolled in the international observational RECage study. Results: The three-factor structure has not been confirmed by the CFA, whilst the EFA was carried out respectively on 25 items disregarding 4 items with a prevalence ≤5% and then on 20 items disregarding 9 items with a prevalence ≤10%. The four-factor structure explaining 56% of the variance comprised Physically Aggressive behavior, Verbally Aggressive behavior, Physically non-aggressive behavior, and Physically and verbally aggressive behavior. Conclusions: A new grouping of all items according to a clinical criterion is proposed, allowing for a more sensible evaluation of the symptoms leading to better differentiation.

Abstract Background Although convolutional neural networks (CNNs) achieve high diagnostic accuracy for detecting Alzheimer’s disease (AD) dementia based on magnetic resonance imaging (MRI) scans, they are not yet applied in clinical routine. One important reason for this is a lack of model comprehensibility. Recently developed visualization methods for deriving CNN relevance maps may help to fill this gap as they allow the visualization of key input image features that drive the decision of the model. We investigated whether models with higher accuracy also rely more on discriminative brain regions predefined by prior knowledge. Methods We trained a CNN for the detection of AD in N = 663 T1-weighted MRI scans of patients with dementia and amnestic mild cognitive impairment (MCI) and verified the accuracy of the models via cross-validation and in three independent samples including in total N = 1655 cases. We evaluated the association of relevance scores and hippocampus volume to validate the clinical utility of this approach. To improve model comprehensibility, we implemented an interactive visualization of 3D CNN relevance maps, thereby allowing intuitive model inspection. Results Across the three independent datasets, group separation showed high accuracy for AD dementia versus controls (AUC ≥ 0.91) and moderate accuracy for amnestic MCI versus controls (AUC ≈ 0.74). Relevance maps indicated that hippocampal atrophy was considered the most informative factor for AD detection, with additional contributions from atrophy in other cortical and subcortical regions. Relevance scores within the hippocampus were highly correlated with hippocampal volumes (Pearson’s r ≈ −0.86, p < 0.001). Conclusion The relevance maps highlighted atrophy in regions that we had hypothesized a priori. This strengthens the comprehensibility of the CNN models, which were trained in a purely data-driven manner based on the scans and diagnosis labels. The high hippocampus relevance scores as well as the high performance achieved in independent samples support the validity of the CNN models in the detection of AD-related MRI abnormalities. The presented data-driven and hypothesis-free CNN modeling approach might provide a useful tool to automatically derive discriminative features for complex diagnostic tasks where clear clinical criteria are still missing, for instance for the differential diagnosis between various types of dementia.

IntroductionSeveral lifestyle factors promote protection against Alzheimer's disease (AD) throughout a person's lifespan. Although such protective effects have been described for occupational cognitive requirements (OCR) in midlife, it is currently unknown whether they are conveyed by brain maintenance (BM), brain reserve (BR), or cognitive reserve (CR) or a combination of them.MethodsWe systematically derived hypotheses for these resilience concepts and tested them in the population-based AgeCoDe cohort and memory clinic-based AD high-risk DELCODE study. The OCR score (OCRS) was measured using job activities based on the O*NET occupational classification system. Four sets of analyses were conducted: (1) the interaction of OCR and APOE-ε4 with regard to cognitive decline (N = 2,369, AgeCoDe), (2) association with differentially shaped retrospective trajectories before the onset of dementia of the Alzheimer's type (DAT; N = 474, AgeCoDe), (3) cross-sectional interaction of the OCR and cerebrospinal fluid (CSF) AD biomarkers and brain structural measures regarding memory function (N = 873, DELCODE), and (4) cross-sectional and longitudinal association of OCR with CSF AD biomarkers and brain structural measures (N = 873, DELCODE).ResultsRegarding (1), higher OCRS was associated with a reduced association of APOE-ε4 with cognitive decline (mean follow-up = 6.03 years), consistent with CR and BR. Regarding (2), high OCRS was associated with a later onset but subsequently stronger cognitive decline in individuals converting to DAT, consistent with CR. Regarding (3), higher OCRS was associated with a weaker association of the CSF Aβ42/40 ratio and hippocampal volume with memory function, consistent with CR. Regarding (4), OCR was not associated with the levels or changes in CSF AD biomarkers (mean follow-up = 2.61 years). We found a cross-sectional, age-independent association of OCRS with some MRI markers, but no association with 1-year-change. OCR was not associated with the intracranial volume. These results are not completely consistent with those of BR or BM.DiscussionOur results support the link between OCR and CR. Promoting and seeking complex and stimulating work conditions in midlife could therefore contribute to increased resistance to pathologies in old age and might complement prevention measures aimed at reducing pathology.

Regular musical activity as a complex multimodal lifestyle activity is proposed to be protective against age-related cognitive decline and Alzheimer’s disease. This cross-sectional study investigated the association and interplay between musical instrument playing during life, multi-domain cognitive abilities and brain morphology in older adults (OA) from the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Participants reporting having played a musical instrument across three life periods (n = 70) were compared to controls without a history of musical instrument playing (n = 70), well-matched for reserve proxies of education, intelligence, socioeconomic status and physical activity. Participants with musical activity outperformed controls in global cognition, working memory, executive functions, language, and visuospatial abilities, with no effects seen for learning and memory. The musically active group had greater gray matter volume in the somatosensory area, but did not differ from controls in higher-order frontal, temporal, or hippocampal volumes. However, the association between gray matter volume in distributed frontal-to-temporal regions and cognitive abilities was enhanced in participants with musical activity compared to controls. We show that playing a musical instrument during life relates to better late-life cognitive abilities and greater brain capacities in OA. Musical activity may serve as a multimodal enrichment strategy that could help preserve cognitive and brain health in late life. Longitudinal and interventional studies are needed to support this notion.

Abstract Background Locating technologies are a subtype of assistive technology that aim to support persons with dementia by helping manage spatial orientation impairments and provide aid to care partners by intervening when necessary. Although a variety of locating devices are commercially available, their adoption has remained low in the past years. Several studies have explored barriers to the adoption of assistive technologies from the perspective of professional stakeholders, but in-depth explorations for locating technologies are sparse. Additionally, the inputs of business professionals are lacking. The aim of this study was to expand knowledge on barriers to the adoption of locating technologies from a multi-stakeholder professional perspective, and to explore strategies to optimize adoption. Methods In total, 22 professionals working in business (n = 7), healthcare (n = 6) and research (n = 9) fields related to gerontology and gerontechnology participated in our focus group study. Perceptions on the value of using locating technologies for dementia care, barriers to their adoption, as well as salient services and information dissemination strategies were explored. After verbatim transcription, transcripts were analysed following an inductive data-driven content analysis approach in MAXQDA. Results Six key adoption barriers centering on: (1) awareness-, (2) technological-, (3) product characteristic- and (4) capital investment-based limitations, (5) unclear benefits, as well as (6) ethical concerns emerged. The interplay between barriers was high. Five core themes on services and information dissemination strategies centering on: (1) digital autonomy support, (2) emergency support, (3) information dissemination actors, (4) product acquisition, and (5) product advertising were extracted. Conclusions Our study with interdisciplinary stakeholders expands knowledge on barriers to the adoption of locating technologies for dementia care, and reinforces recommendations that an interdisciplinary strategy is needed to optimize adoption. Also, our findings show that focusing on services to increase digital autonomy and on information dissemination strategies has been largely overlooked and may be particularly effective.

Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.

Abstract Background Early identification of individuals at risk of dementia is mandatory to implement prevention strategies and design clinical trials that target early disease stages. Subjective cognitive decline (SCD) and neuropsychiatric symptoms (NPS) have been proposed as potential markers for early manifestation of Alzheimer’s disease (AD). We aimed to investigate the frequency of NPS in SCD, in other at-risk groups, in healthy controls (CO), and in AD patients, and to test the association of NPS with AD biomarkers, with a particular focus on cognitively unimpaired participants with or without SCD-related worries. Methods We analyzed data of n = 687 participants from the German DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study, including the diagnostic groups SCD (n = 242), mild cognitive impairment (MCI, n = 115), AD (n = 77), CO (n = 209), and first-degree relatives of AD patients (REL, n = 44). The Neuropsychiatric Inventory Questionnaire (NPI-Q), Geriatric Depression Scale (GDS-15), and Geriatric Anxiety Inventory (GAI-SF) were used to assess NPS. We examined differences of NPS frequency between diagnostic groups. Logistic regression analyses were carried out to further investigate the relationship between NPS and cerebrospinal fluid (CSF) AD biomarkers, focusing on a subsample of cognitively unimpaired participants (SCD, REL, and CO), who were further differentiated based on reported worries. Results The numbers of reported NPS, depression scores, and anxiety scores were significantly higher in subjects with SCD compared to CO. The quantity of reported NPS in subjects with SCD was lower compared to the MCI and AD group. In cognitively unimpaired subjects with worries, low Aß42 was associated with higher rates of reporting two or more NPS (OR 0.998, 95% CI 0.996–1.000, p

Abstract Background Late-life depression (LLD) is one of the most prevalent mental disorders in old age. It is associated with various adverse outcomes and frequent use of health care services thereby remaining a serious public health concern. Compared with depression in early adulthood, most treatment options of LLD are less effective. Psychotherapy may be particularly beneficial for LLD due to specific psychological conditions in old age and a low risk of side effects. Although cognitive behavioural therapy (CBT) is highly established and effective in depression in young and mid-life there is only a limited number of small studies on CBT in LLD. An LLD-specific CBT has not yet been compared to an active, but unspecific supportive psychological intervention in a multicentre trial. Methods Here we present the design of the CBTlate trial, which is a multicentre, randomized, observer-blinded, active-controlled, parallel group trial. CBTlate aims at including 248 patients with LLD of both genders at 7 sites in Germany. The purpose of the study is to test the hypothesis that a 15-session individually-delivered CBT specific for LLD is of superior efficacy in reducing symptoms of depression in comparison with a supportive unspecific intervention (SUI) of the same quantity. The intervention includes 8 weeks of individual treatment sessions twice per week and a follow-up period of 6 months after randomization. The primary end point is the severity of depression at the end of treatment measured by the self-rated 30-item Geriatric Depression Scale (GDS). Secondary endpoints include depressive symptoms at week 5 and at follow-up (6 months after randomization). Additional secondary endpoints include the change of depressive symptoms assessed with a clinician-rating-scale and a patient reported outcome instrument for major depressive disorder, anxiety symptoms, sleep, cognition, quality of life, and overall health status from baseline to end-of treatment and to end of follow-up. Add-on protocols include MRI and the collection of blood samples. Discussion This study is the first multicentre trial of a specific CBT intervention for LLD compared to an unspecific supportive psychological intervention administered in a specialist setting. It has important implications for developing and implementing efficient psychotherapeutic strategies for LLD and may be a significant step to broaden treatment options for people suffering from LLD. Trial registration ClinicalTrials.gov (NCT03735576, registered on 24 October 2018); DRKS (DRKS00013769, registered on 28 June 2018).

Abstract Introduction Impaired long‐term memory is a defining feature of mild cognitive impairment (MCI). We tested whether this impairment is item specific, limited to some memoranda, whereas some remain consistently memorable. Methods We conducted item‐based analyses of long‐term visual recognition memory. Three hundred ninety‐four participants (healthy controls, subjective cognitive decline [SCD], and MCI) in the multicentric DZNE‐Longitudinal Cognitive Impairment and Dementia Study (DELCODE) were tested with images from a pool of 835 photographs. Results We observed consistent memorability for images in healthy controls, SCD, and MCI, predictable by a neural network trained on another healthy sample. Looking at memorability differences between groups, we identified images that could successfully categorize group membership with higher success and a substantial image reduction than the original image set. Discussion Individuals with SCD and MCI show consistent memorability for specific items, while other items show significant diagnosticity. Certain stimulus features could optimize diagnostic assessment, while others could support memory.

Abstract While some individuals age without pathological memory impairments, others develop age‐associated cognitive diseases. Since changes in cognitive function develop slowly over time in these patients, they are often diagnosed at an advanced stage of molecular pathology, a time point when causative treatments fail. Thus, there is great need for the identification of inexpensive and minimal invasive approaches that could be used for screening with the aim to identify individuals at risk for cognitive decline that can then undergo further diagnostics and eventually stratified therapies. In this study, we use an integrative approach combining the analysis of human data and mechanistic studies in model systems to identify a circulating 3‐microRNA signature that reflects key processes linked to neural homeostasis and inform about cognitive status. We furthermore provide evidence that expression changes in this signature represent multiple mechanisms deregulated in the aging and diseased brain and are a suitable target for RNA therapeutics.

Objective markers for the neurodegenerative disorder progressive supranuclear palsy (PSP) are needed to provide a timely diagnosis with greater certainty. Non-coding RNA (ncRNA), including microRNA, piwi-interacting RNA, and transfer RNA, are good candidate markers in other neurodegenerative diseases, but have not been investigated in PSP. Therefore, as proof of principle, we sought to identify whether they were dysregulated in matched serum and cerebrospinal fluid (CSF) samples of patients with PSP. Small RNA-seq was undertaken on serum and CSF samples from healthy controls (n = 20) and patients with PSP (n = 31) in two cohorts, with reverse transcription-quantitative PCR (RT-qPCR) to confirm their dysregulation. Using RT-qPCR, we found in serum significant down-regulation in hsa-miR-92a-3p, hsa-miR-626, hsa-piR-31068, and tRNA-ValCAC. In CSF, both hsa-let-7a-5p and hsa-piR-31068 showed significant up-regulation, consistent with their changes observed in the RNA-seq results. Interestingly, we saw no correlation in the expression of hsa-piR-31068 within our matched serum and CSF samples, suggesting there is no common dysregulatory mechanism between the two biofluids. While these changes were in a small cohort of samples, we have provided novel evidence that ncRNA in biofluids could be possible diagnostic biomarkers for PSP and further work will help to expand this potential.

Objective To assess the SARS-CoV-2 transmission in healthcare workers (HCWs) using seroprevalence as a surrogate marker of infection in our tertiary care centre according to exposure.Design Seroprevalence cross-sectional study.Setting Single centre at the end of the first COVID-19 wave in Lausanne, Switzerland.Participants 1874 of 4074 responders randomly selected (46% response rate), stratified by work category among the 13 474 (13.9%) HCWs.Main outcome measures Evaluation of SARS-CoV-2 serostatus paired with a questionnaire of SARS-CoV-2 acquisition risk factors internal and external to the workplace.Results The overall SARS-CoV-2 seroprevalence rate among HCWs was 10.0% (95% CI 8.7% to 11.5%). HCWs with daily patient contact did not experience increased rates of seropositivity relative to those without (10.3% vs 9.6%, respectively, p=0.64). HCWs with direct contact with patients with COVID-19 or working in COVID-19 units did not experience increased seropositivity rates relative to their counterparts (10.4% vs 9.8%, p=0.69 and 10.6% vs 9.9%, p=0.69, respectively). However, specific locations of contact with patients irrespective of COVID-19 status—in patient rooms or reception areas—did correlate with increased rates of seropositivity (11.9% vs 7.5%, p=0.019 and 14.3% vs 9.2%, p=0.025, respectively). In contrast, HCWs with a suspected or proven SARS-CoV-2-infected household contact had significantly higher seropositivity rates than those without such contacts (19.0% vs 8.7%, p

Background: The hippocampus and its subfields (HippSub) are reported to be diminished in patients with Alzheimer's disease (AD), bipolar disorder (BD), and major depressive disorder (MDD). We examined these groups vs healthy controls (HC) to reveal HippSub alterations between diseases.Methods: We segmented 3T-MRI T2-weighted hippocampal images of 67 HC, 58 BD, and MDD patients from the AFFDIS study and 137 patients from the DELCODE study assessing cognitive decline, including subjective cognitive decline (SCD), amnestic mild cognitive impairment (aMCI), and AD, via Free Surfer 6.0 to compare volumes across groups.Results: Groups differed significantly in several HippSub volumes, particularly between patients with AD and mood disorders. In comparison to HC, significant lower volumes appear in aMCI and AD groups in specific subfields. Smaller volumes in the left presubiculum are detected in aMCI and AD patients, differing from the BD group. A significant linear regression is seen between left hippocampus volume and duration since the first depressive episode.Conclusions: HippSub volume alterations were observed in AD, but not in early-onset MDD and BD, reinforcing the notion of different neural mechanisms in hippocampal degeneration. Moreover, duration since the first depressive episode was a relevant factor explaining the lower left hippocampal volumes present in groups.

Abstract Background Subjective cognitive decline (SCD) has been proposed as a pre-MCI at-risk condition of Alzheimer’s disease (AD). Current research is focusing on a refined assessment of specific SCD features associated with increased risk for AD, as proposed in the SCD-plus criteria. We developed a structured interview (SCD-I) for the assessment of these features and tested their relationship with AD biomarkers. Methods We analyzed data of 205 cognitively normal participants of the DELCODE study (mean age = 68.9 years; 52% female) with available CSF AD biomarkers (Aß-42, p-Tau181, Aß-42/Tau ratio, total Tau). For each of five cognitive domains (including memory, language, attention, planning, others), a study physician asked participants about the following SCD-plus features: the presence of subjective decline, associated worries, onset of SCD, feeling of worse performance than others of the same age group, and informant confirmation. We compared AD biomarkers of subjects endorsing each of these questions with those who did not, controlling for age. SCD was also quantified by two summary scores: the number of fulfilled SCD-plus features, and the number of domains with experienced decline. Covariate-adjusted linear regression analyses were used to test whether these SCD scores predicted abnormality in AD biomarkers. Results Lower Aß-42 levels were associated with a reported decline in memory and language abilities, and with the following SCD-plus features: onset of subjective decline within 5 years, confirmation of cognitive decline by an informant, and decline-related worries. Furthermore, both quantitative SCD scores were associated with lower Aß42 and lower Aß42/Tau ratio, but not with total Tau or p-Tau181. Conclusions Findings support the usefulness of a criterion-based interview approach to assess and quantify SCD in the context of AD and validate the current SCD-plus features as predictors of AD pathology. While some features seem to be more closely associated with AD biomarkers than others, aggregated scores over several SCD-plus features or SCD domains may be the best predictors of AD pathology.

Abstract Background Biomarkers such as cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) have predictive value for progression to dementia in patients with mild cognitive impairment (MCI). The pre-dementia stage takes far longer, and the interpretation of biomarker findings is particular relevant for individuals who present at a memory clinic, but are deemed cognitively normal. The objective of the current study is to construct biomarker-based prognostic models for personalized risk of clinical progression in cognitively normal individuals presenting at a memory clinic. Methods We included 481 individuals with subjective cognitive decline (SCD) from the Amsterdam Dementia Cohort. Prognostic models were developed by Cox regression with patient characteristics, MRI, and/or CSF biomarkers to predict clinical progression to MCI or dementia. We estimated 5- and 3-year individualized risks based on patient-specific values. External validation was performed on Alzheimer’s Disease Neuroimaging Initiative (ADNI) and an European dataset. Results Based on demographics only (Harrell’s C = 0.70), 5- and 3-year progression risks varied from 6% [3–11] and 4% [2–8] (age 55, MMSE 30) to 38% [29–49] and 28% [21–37] (age 70, MMSE 27). Normal CSF biomarkers strongly decreased progression probabilities (Harrell’s C = 0.82). By contrast, abnormal CSF markedly increased risk (5 years, 96% [56–100]; 3 years, 89% [44–99]). The CSF model could reclassify 58% of the individuals with an “intermediate” risk (35–65%) based on the demographic model. MRI measures were not retained in the models. Conclusion The current study takes the first steps in a personalized approach for cognitively normal individuals by providing biomarker-based prognostic models.

Abstract Introduction Subjective cognitive decline (SCD) in cognitively unimpaired older individuals has been recognized as an early clinical at-risk state for Alzheimer’s disease (AD) dementia and as a target population for future dementia prevention trials. Currently, however, SCD is heterogeneously defined across studies, potentially leading to variations in the prevalence of AD pathology. Here, we compared the prevalence and identified common determinants of abnormal AD biomarkers in SCD across three European memory clinics participating in the European initiative on harmonization of SCD in preclinical AD (Euro-SCD). Methods We included three memory clinic SCD samples with available cerebrospinal fluid (CSF) biomaterial (IDIBAPS, Barcelona, Spain, n = 44; Amsterdam Dementia Cohort (ADC), The Netherlands, n = 50; DELCODE multicenter study, Germany, n = 42). CSF biomarkers (amyloid beta (Aβ)42, tau, and phosphorylated tau (ptau181)) were centrally analyzed in Amsterdam using prespecified cutoffs to define prevalence of pathological biomarker concentrations. We used logistic regression analysis in the combined sample across the three centers to investigate center effects with regard to likelihood of biomarker abnormality while taking potential common predictors (e.g., age, sex, apolipoprotein E (APOE) status, subtle cognitive deficits, depressive symptoms) into account. Results The prevalence of abnormal Aβ42, but not tau or ptau181, levels was different across centers (64% DELCODE, 57% IDIBAPS, 22% ADC; p

Abstract Background Enhanced Recovery After Surgery (ERAS) is a perioperative management based on multimodality and multidisciplinary work. ERAS has been shown to have important clinical and economic benefits, but its spread remains slow worldwide. Discussion This manuscript reviews the overall program benefits and focuses on important aspects for implementation well beyond surgery. Summary Implementation of ERAS pathways improves clinical outcomes and induces substantial economic gains. ERAS is the current surgical revolution.

Background: Cognitive decline has been found to be associated with gray matter atrophy and disruption of functional neural networks in Alzheimer’s disease (AD) in structural and functional imaging (fMRI) studies. Most previous studies have used single test scores of cognitive performance among monocentric cohorts. However, cognitive domain composite scores could be more reliable than single test scores due to the reduction of measurement error. Adopting a multicentric resting state fMRI (rs-fMRI) and cognitive domain approach, we provide a comprehensive description of the structural and functional correlates of the key cognitive domains of AD. Method: We analyzed MRI, rs-fMRI and cognitive domain score data of 490 participants from an interim baseline release of the multicenter DELCODE study cohort, including 54 people with AD, 86 with Mild Cognitive Impairment (MCI), 175 with Subjective Cognitive Decline (SCD), and 175 Healthy Controls (HC) in the AD-spectrum. Resulting cognitive domain composite scores (executive, visuo-spatial, memory, working memory and language) from the DELCODE neuropsychological battery (DELCODE-NP), were previously derived using confirmatory factor analysis. Statistical analyses examined the differences between diagnostic groups, and the association of composite scores with regional atrophy and network-specific functional connectivity among the patient subgroup of SCD, MCI and AD. Result: Cognitive performance, atrophy patterns and functional connectivity significantly differed between diagnostic groups in the AD-spectrum. Regional gray matter atrophy was positively associated with visuospatial and other cognitive impairments among the patient subgroup in the AD-spectrum. Except for the visual network, patterns of network-specific resting-state functional connectivity were positively associated with distinct cognitive impairments among the patient subgroup in the AD-spectrum. Conclusion: Consistent associations between cognitive domain scores and both regional atrophy and network-specific functional connectivity (except for the visual network), support the utility of a multicentric and cognitive domain approach towards explicating the relationship between imaging markers and cognition in the AD-spectrum.

Abstract Introduction Large studies on cognitive profiles of patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD‐MCI) compared to Parkinson's disease (PD‐MCI) are rare. Methods Data from two multicenter cohort studies in AD and PD were merged using a unified base rate approach for the MCI diagnosis. Cognitive profiles were compared using scores derived from the Consortium to Establish a Registry for Alzheimer's Disease battery. Results Patients with AD‐MCI showed lower standardized scores on all memory test scores and a language test. Patients with PD‐MCI showed lower standardized scores in a set‐shifting measure as an executive task. A cross‐validated logistic regression with test scores as predictors was able to classify 72% of patients correctly to AD‐MCI versus PD‐MCI. Discussion The applied test battery successfully discriminated between AD‐MCI and PD‐MCI. Neuropsychological test batteries in clinical practice should always include a broad spectrum of cognitive domains to capture any cognitive changes.

Abstract Neurodegenerative diseases are a growing burden, and there is an urgent need for better biomarkers for diagnosis, prognosis, and treatment efficacy. Structural and functional brain alterations are reflected in the protein composition of cerebrospinal fluid (CSF). Alzheimer's disease (AD) patients have higher CSF levels of tau, but we lack knowledge of systems‐wide changes of CSF protein levels that accompany AD. Here, we present a highly reproducible mass spectrometry (MS)‐based proteomics workflow for the in‐depth analysis of CSF from minimal sample amounts. From three independent studies (197 individuals), we characterize differences in proteins by AD status (> 1,000 proteins, CV

Background: Dysfunction of the cholinergic basal forebrain (cBF) is associated with cognitive decline in Alzheimer’s disease (AD). Multimodal MRI allows for the investigation of cBF changes in-vivo. In this study we assessed alterations in cBF functional connectivity (FC), mean diffusivity (MD), and volume across the spectrum of AD. We further assessed effects of amyloid pathology on these changes. Methods: Participants included healthy controls, and subjects with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or AD dementia (ADD) from the multicenter DELCODE study. Resting-state functional MRI (rs-fMRI) and structural MRI data was available for 477 subjects, and a subset of 243 subjects also had DTI data available. Differences between diagnostic groups were investigated using seed-based FC, volumetric, and MD analyses of functionally defined anterior (a-cBF) and posterior (p-cBF) subdivisions of a cytoarchitectonic cBF region-of-interest. In complementary analyses groups were stratified according to amyloid status based on CSF Aβ42/40 biomarker data, which was available in a subset of participants. Results: a-cBF and p-cBF subdivisions showed regional FC profiles that were highly consistent with previously reported patterns, but there were only minimal differences between diagnostic groups. Compared to controls, cBF volumes and MD were significantly different in MCI and ADD but not in SCD. The Aβ42/40 stratified analyses largely matched these results. Conclusions: We reproduced subregion-specific FC profiles of the cBF in a clinical sample spanning the AD spectrum. At least in this multicentric cohort study, cBF-FC did not show marked changes along the AD spectrum, and multimodal MRI did not provide more sensitive measures of AD-related cBF changes compared to volumetry.

Background/Aims: Major depressive disorder (MDD) can cooccur with early Alzheimer’s disease (AD) or may cause memory problems independently of AD. Previous studies have suggested that the AD-related cerebrospinal fluid (CSF) biomarkers tau and Aβ(1–42) could help discriminate between early AD and depression unrelated to AD. Moreover, the postsynaptic protein neurogranin and presynaptic BACE1 have increasingly gained attention as potential new AD biomarkers, but they have not yet been investigated concerning depression. Methods: Using ELISAs, we studied CSF neurogranin and BACE1 levels in patients with mild (n = 21) and moderate (n = 19) AD, as well as in MDD patients with (n = 20) and without (n = 20) cognitive deficits. The clinical examinations included analyses of t-tau, Aβ(1–42), and Aβ(1–40), besides neuropsychological tests and cranial magnetic resonance imaging. Depressive symptom severity was assessed using the Geriatric Depression Scale (GDS). Results: Along with classic AD biomarkers, neurogranin and BACE1 CSF levels differed between moderate AD and MDD (p ≤ 0.01). MDD associated with cognitive deficits was distinguished from mild AD through the CSF neurogranin/BACE1 ratio (p < 0.05), which was strongly correlated with GDS scores (ρ = –0.656; p < 0.01). Conclusion: The neurogranin/BACE1 ratio in CSF can distinguish between depression and AD among patients with similar cognitive deficits, along with the classic AD biomarkers. Further longitudinal studies are ongoing to identify which biomarkers have prognostic value.

Abstract Background Deep phenotyping and longitudinal assessment of predementia at-risk states of Alzheimer’s disease (AD) are required to define populations and outcomes for dementia prevention trials. Subjective cognitive decline (SCD) is a pre-mild cognitive impairment (pre-MCI) at-risk state of dementia, which emerges as a highly promising target for AD prevention. Methods The German Center for Neurodegenerative Diseases (DZNE) is conducting the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE), which focuses on the characterization of SCD in patients recruited from memory clinics. In addition, individuals with amnestic MCI, mild Alzheimer’s dementia patients, first-degree relatives of patients with Alzheimer’s dementia, and cognitively unimpaired control subjects are studied. The total number of subjects to be enrolled is 1000. Participants receive extensive clinical and neuropsychological assessments, magnetic resonance imaging, positron emission tomography, and biomaterial collection is perfomed. In this publication, we report cognitive and clinical data as well as apolipoprotein E (APOE) genotype and cerebrospinal fluid (CSF) biomarker results of the first 394 baseline data sets. Results In comparison with the control group, patients with SCD showed slightly poorer performance on cognitive and functional measures (Alzheimer’s Disease Assessment Scale—cognitive part, Clinical Dementia Rating, Functional Activities Questionnaire), with all mean scores in a range which would be considered unimpaired. APOE4 genotype was enriched in the SCD group in comparison to what would be expected in the population and the frequency was significantly higher in comparison to the control group. CSF Aβ42 was lower in the SCD group in comparison to the control group at a statistical trend with age as a covariate. There were no group differences in Tau or pTau concentrations between the SCD and the control groups. The differences in all measures between the MCI group and the AD group were as expected. Conclusions The initial baseline data for DELCODE support the approach of using SCD in patients recruited through memory clinics as an enrichment strategy for late-stage preclinical AD. This is indicated by slightly lower performance in a range of measures in SCD in comparison to the control subjects as well as by enriched APOE4 frequency and lower CSF Aβ42 concentration. Trial registration German Clinical Trials Register DRKS00007966. Registered 4 May 2015.

Abstract Introduction Individuals with subjective cognitive decline (SCD) are at increased risk for clinical progression. We studied how combining different diagnostic tests can help to identify individuals who are likely to show clinical progression. Methods We included 674 patients with SCD (46% female, 64 ± 9 years, Mini–Mental State Examination 28 ± 2) from three memory clinic cohorts. A multivariate model based on the Disease State Index classifier incorporated the available baseline tests to predict progression to MCI or dementia over time. We developed and internally validated the model in one cohort and externally validated it in the other cohorts. Results After 2.9 ± 2.0 years, 151(22%) patients showed clinical progression. Overall performance of the classifier when combining cognitive tests, magnetic resonance imagining, and cerebrospinal fluid showed a balanced accuracy of 74.0 ± 5.5, with high negative predictive value (93.3 ± 2.8). Discussion We found that a combination of diagnostic tests helps to identify individuals at risk of progression. The classifier had particularly good accuracy in identifying patients who remained stable.

Abstract Introduction We examined the association between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, neural novelty responses, and brain volume in predementia old age. Methods We conducted a cross‐sectional analysis of the observational, multicentric DZNE‐Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Seventy‐six participants completed task functional magnetic resonance imaging and provided CSF (40 cognitively unimpaired, 21 experiencing subjective cognitive decline, and 15 with mild cognitive impairment). We assessed the correlation between CSF biomarkers and whole‐brain functional magnetic resonance imaging novelty responses to scene images. Results Total tau levels were specifically and negatively associated with novelty responses in the right amygdala and right hippocampus. Mediation analyses showed no evidence that these associations were dependent on the volume of hippocampus/amygdala. No relationship was found between phosphorylated‐tau or Aβ42 levels and novelty responses. Discussion Our data show that CSF levels of total tau are associated with anatomically specific reductions in novelty processing, which cannot be fully explained by atrophy.

Abstract Background The progression of mild cognitive impairment (MCI) to Alzheimer’s disease (AD) dementia can be predicted by cognitive, neuroimaging, and cerebrospinal fluid (CSF) markers. Since most biomarkers reveal complementary information, a combination of biomarkers may increase the predictive power. We investigated which combination of the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR)-sum-of-boxes, the word list delayed free recall from the Consortium to Establish a Registry of Dementia (CERAD) test battery, hippocampal volume (HCV), amyloid-beta1–42 (Aβ42), amyloid-beta1–40 (Aβ40) levels, the ratio of Aβ42/Aβ40, phosphorylated tau, and total tau (t-Tau) levels in the CSF best predicted a short-term conversion from MCI to AD dementia. Methods We used 115 complete datasets from MCI patients of the “Dementia Competence Network”, a German multicenter cohort study with annual follow-up up to 3 years. MCI was broadly defined to include amnestic and nonamnestic syndromes. Variables known to predict progression in MCI patients were selected a priori. Nine individual predictors were compared by receiver operating characteristic (ROC) curve analysis. ROC curves of the five best two-, three-, and four-parameter combinations were analyzed for significant superiority by a bootstrapping wrapper around a support vector machine with linear kernel. The incremental value of combinations was tested for statistical significance by comparing the specificities of the different classifiers at a given sensitivity of 85%. Results Out of 115 subjects, 28 (24.3%) with MCI progressed to AD dementia within a mean follow-up period of 25.5 months. At baseline, MCI-AD patients were no different from stable MCI in age and gender distribution, but had lower educational attainment. All single biomarkers were significantly different between the two groups at baseline. ROC curves of the individual predictors gave areas under the curve (AUC) between 0.66 and 0.77, and all single predictors were statistically superior to Aβ40. The AUC of the two-parameter combinations ranged from 0.77 to 0.81. The three-parameter combinations ranged from AUC 0.80–0.83, and the four-parameter combination from AUC 0.81–0.82. None of the predictor combinations was significantly superior to the two best single predictors (HCV and t-Tau). When maximizing the AUC differences by fixing sensitivity at 85%, the two- to four-parameter combinations were superior to HCV alone. Conclusion A combination of two biomarkers of neurodegeneration (e.g., HCV and t-Tau) is not superior over the single parameters in identifying patients with MCI who are most likely to progress to AD dementia, although there is a gradual increase in the statistical measures across increasing biomarker combinations. This may have implications for clinical diagnosis and for selecting subjects for participation in clinical trials.

Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.

The role of genetic risk markers for Alzheimer’s disease (AD) in mediating the neurocognitive endophenotypes (NEs) of subjects with mild cognitive impairment (MCI) has rarely been studied. The aim of the present study was to investigate the relationship between well-known AD-associated single-nucleotide polymorphisms (SNPs) and individual NEs routinely evaluated during diagnosis of MCI, AD, and other dementias. The Fundació ACE (ACE) dataset, comprising information from 1245 patients with MCI, was analyzed, including the total sample, amnestic MCI (aMCI) (n = 811), and non-amnestic MCI (naMCI) (n = 434). As probable-MCI (Pr-MCI) patients with memory impairment have a higher risk of AD, which could influence the statistical power to detect genetic associations, the MCI phenotype was also stratified into four related conditions: Pr-aMCI (n = 262), Pr-naMCI (n = 76), possible (Pss)-aMCI (n = 549), and Pss-naMCI (n = 358). Validation analyses were performed using data from the German study on Aging, Cognition, and Dementia in primary care patients (AgeCoDe), and the German Dementia Competence Network (DCN). SNP associations with NEs were calculated in PLINK using multivariate linear regression analysis adjusted for age, gender, and education. In the total MCI sample, APOE-ε4 was significantly associated with the memory function NEs “delayed recall (DR)” (β = -0.76, p = 4.1 × 10-10), “learning” (β = -1.35, p = 2.91 × 10-6), and “recognition memory” (β = -0.58, p = 9.67 × 10-5); and with “DR” in the aMCI group (β = -0.36, p = 2.96 × 10-5). These results were confirmed by validation in the AgeCoDe (n = 503) and DCN (n = 583) datasets. APOE-ε4 was also significantly associated with the NE “learning” in individuals classified as having Pss-aMCI (β = -1.37, p = 5.82 × 10-5). Moreover, there was a near study-wide significant association between the HS3ST1 locus (rs6448799) and the “backward digits” working memory NE (β = 0.52, p = 7.57 × 10-5) among individuals with Pr-aMCI, while the AP2A2 locus (rs10751667) was significantly associated with the language NE “repetition” (β = -0.19, p = 5.34 × 10-6). Overall, our findings support specific associations of established AD-associated SNPs with MCI NEs.

NMR-based metabolomics investigations of human biofluids offer great potential to uncover new biomarkers. In contrast to protocols for sample collection and biobanking, procedures for sample preparation prior to NMR measurements are still heterogeneous, thus compromising the comparability of the resulting data. Herein, we present results of an investigation of the handling of cerebrospinal fluid (CSF) samples for NMR metabolomics research. Origins of commonly observed problems when conducting NMR experiments on this type of sample are addressed, and suitable experimental conditions in terms of sample preparation and pH control are discussed. Sample stability was assessed by monitoring the degradation of CSF samples by NMR, hereby identifying metabolite candidates, which are potentially affected by sample storage. A protocol was devised yielding consistent spectroscopic data as well as achieving overall sample stability for robust analysis. We present easy to adopt standard operating procedures with the aim to establish a shared sample handling strategy that facilitates and promotes inter-laboratory comparison, and the analysis of sample degradation provides new insights into sample stability.

MicroRNAs (miRNAs) are non-coding RNAs originally involved in RNA silencing and post-transcriptional regulation of gene expression. We have shown in previous work that the miRNA let-7b can act as a signalling molecule for Toll-like receptor 7, thereby initiating innate immune pathways and apoptosis in the central nervous system. Here, we investigated whether different members of the miRNA family let-7, abundantly expressed in the brain, are released into the human cerebrospinal fluid (CSF) and whether quantitative differences in let-7 copies exist in neurodegenerative diseases. RNA isolated from CSF of patients with Alzheimer´s disease (AD) and from control patients with frontotemporal lobe dementia (FTLD), major depressive episode (MDE) without clinical or neurobiological signs of AD, and healthy individuals, was reverse transcribed with primers against nine let-7 family members, and miRNAs were quantified and analyzed comparatively by quantitative PCR. let-7 miRNAs were present in CSF from patients with AD, FTLD, MDE, and healthy controls. However, the amount of individual let-7 miRNAs in the CSF varied substantially. CSF from AD patients contained higher amounts of let-7b and let-7e compared to healthy controls, while no differences were observed regarding the other let-7 miRNAs. No increase in let-7b and let-7e was detected in CSF from FTLD patients, while in CSF from MDE patients, let-7b and let-7e copy levels were elevated. In CSF from AD patients, let-7b and let-7e were associated with extracellular vesicles. let-7 family members present in the CSF mediated neurotoxicity in vitro, albeit to a variable extent. Taken together, neurotoxic let-7 miRNAs are differentially and specifically released in AD, but also in MDE patients. Thus, these miRNAs may mirror common neuropathological paths and by this serve to unscramble mechanisms of different neurodegenerative diseases.

Covalently closed circular RNA molecules (circRNAs) have recently emerged as a class of RNA isoforms with widespread and tissue specific expression across animals, oftentimes independent of the corresponding linear mRNAs. circRNAs are remarkably stable and sometimes highly expressed molecules. Here, we sequenced RNA in human peripheral whole blood to determine the potential of circRNAs as biomarkers in an easily accessible body fluid. We report the reproducible detection of thousands of circRNAs. Importantly, we observed that hundreds of circRNAs are much higher expressed than corresponding linear mRNAs. Thus, circRNA expression in human blood reveals and quantifies the activity of hundreds of coding genes not accessible by classical mRNA specific assays. Our findings suggest that circRNAs could be used as biomarker molecules in standard clinical blood samples.

All actually used SAW sensors have in common that they analyze the transmission characteristics of propagating SAWs. Here, a portable device using the SAW-based impedance sensor type based on one interdigital transducer (IDT) simultaneously as SAW generator and sensor element (1-port approach) is presented. The input port reflection coefficient S11 is measured at the IDT instead of the commonly used S21 transmission forward gain parameter. As a novelty, the so far required expensive vector network analyzer (VNA) is replaced by a hand-held device to measure the impedance spectrum of the SAW sensor by RF-gain-phase meters. The pivotal aspect of the portable system is the transfer of the sophisticated high frequency approach into a quasi-static one. This enables the use of simple lumped electronics without the need of impedance matching circuits. Proof-of-concept was carried out by measuring conductivities of phosphate-buffered solutions (PBS) and viscosities of glycerin. Sensitivities for conductivity of 64 Hz/S cm−1 and for viscosity of 122 mΩ/mPas were obtained, respectively.