Replication study of plasma proteins relating to Alzheimer's pathology.

INTRODUCTION: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. METHODS: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively. RESULTS: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis. DISCUSSION: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.

Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology.

BACKGROUND: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. OBJECTIVE: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. METHODS: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). RESULTS: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. CONCLUSIONS: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.

Validation of replacement questions for slowness and weakness to assess the Fried Phenotype: a cross-sectional study.

PURPOSE: When screening large populations, performance-based measures can be difficult to conduct because they are time consuming and costly, and require well-trained assessors. The aim of the present study is to validate a set of questions replacing the performance-based measures slowness and weakness as part of the Fried frailty phenotype (FRIED-P). METHODS: A cross-sectional study was conducted among community-dwelling older adults (≥ 60 years) in three Flemish municipalities. The Fried Phenotype (FRIED-P) was used to measure physical frailty. The two performance-based measures of the Fried Phenotype (slowness and weakness) were also measured by means of six substituting questions (FRIED-Q). These questions were validated through sensitivity, specificity, Cohen's kappa value, observed agreement, correlation analysis, and the area under the curve (AUC, ROC curve). RESULTS: 196 older adults participated. According to the FRIED-P, 19.5% of them were frail, 56.9% were pre-frail and 23.6% were non-frail. For slowness, the observed sensitivity was 47.0%, the specificity was 96.5% and the AUC was 0.717. For weakness, the sensitivity was 46.2%, the specificity was 83.7%, and the AUC was 0.649. The overall Spearman correlation between the FRIED-P and the FRIED-Q was r = 0.721 with an observed agreement of 76.6% (weighted linear kappa value = 0.663, quadratic kappa value = 0.738). CONCLUSIONS: The concordance between the FRIED-P and FRIED-Q was substantial, characterized by a very high specificity, but a moderate sensitivity. This alternative operationalization of the Fried Phenotype-i.e., including six replacement questions instead of two performance-based tests-can be considered to apply as screening tool to screen physical frailty in large populations.

Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort.

We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.

Exploring Cognitive Frailty: Prevalence and Associations with Other Frailty Domains in Older People with Different Degrees of Cognitive Impairment.

BACKGROUND: Cognitive frailty has long been defined as the co-occurrence of mild cognitive deficits and physical frailty. However, recently, a new approach to cognitive frailty has been proposed: cognitive frailty as a distinct construct. Nonetheless, the relationship between this relatively new construct of cognitive frailty and other frailty domains is unclear. OBJECTIVES: The aims of this study were to explore the prevalence of cognitive frailty in groups with different degrees of cognitive impairment, as well as to explore the associations between frailty domains, and if this varies with level of objective cognitive impairment. METHOD: Cross-sectional, secondary data from 3 research projects among community-dwelling people aged ≥60 years, with different degrees of objective cognitive impairment, were used: (1) a randomly selected sample (n = 353); (2) a sample at an increased risk of frailty (n = 95); and (3) a sample of memory clinic patients who scored 0.5 on the Clinical Dementia Rating scale - according to the "original" definition of cognitive frailty (n = 47). Multidimensional frailty was assessed with the Comprehensive Frailty Assessment Instrument - Plus and general cognitive functioning with the Montreal Cognitive Assessment. Descriptive statistics and linear regression were used to determine the prevalence of cognitive frailty and to explore the relationship between cognitive frailty and the other types of frailty in each sample. RESULTS: The prevalence of cognitive frailty increased along with the degree of objective cognitive impairment in the 3 samples (range 35.1-80.9%), while its co-occurrence with (one of) the other types of frailty was most frequent in the frail and community samples. Regarding its relationship with the other domains, cognitive frailty was positively associated with psychological frailty's subdomain mood disorder symptoms in all 3 samples (p ≤ 0.01), while there was no significant association with environmental frailty and social loneliness. The associations between cognitive frailty and the other types of frailty differed between the samples. CONCLUSION: Psychological and cognitive frailty are strongly associated, irrespective of the objective degree of cognitive impairment. In addition, it is shown that cognitive frailty can occur independently from the other frailty domains, including physical frailty, and therefore it can be seen as a distinct concept.

Concordances and differences between a unidimensional and multidimensional assessment of frailty: a cross-sectional study.

BACKGROUND: Many instruments to identify frail older people have been developed. One of the consequences is that the prevalence rates of frailty vary widely dependent on the instrument selected. The aims of this study were 1) to examine the concordances and differences between a unidimensional and multidimensional assessment of frailty, 2) to assess to what extent the characteristics of a 'frail sample' differ depending on the selected frailty measurement because 'being frail' is used in many studies as an inclusion criterion. METHOD: A cross-sectional study was conducted among 196 community-dwelling older adults (≥60 years), which were selected from the census records. Unidimensional frailty was operationalized according to the Fried Phenotype (FP) and multidimensional frailty was measured with the Comprehensive Frailty Assessment Instrument (CFAI). The concordances and differences were examined by prevalence, correlations, observed agreement and Kappa values. Differences between sample characteristics (e.g., age, physical activity, life satisfaction) were investigated with ANOVA and Kruskall-Wallis test. RESULTS: The mean age was 72.74 (SD 8.04) and 48.98% was male. According to the FP 23.59% was not-frail, 56.92% pre-frail and 19.49% frail. According to the CFAI, 44.33% was no-to-low frail, 37.63% was mild frail and 18.04% was high frail. The correlation between FP and the CFAI was r = 0.46 and the observed agreement was 52.85%. The Kappa value was κ = 0.35 (quadratic κ = 0.45). In total, 11.92% of the participants were frail according to both measurements, 7.77% was solely frail according to the FP and 6.21% was solely frail according to the CFAI. The 'frail sample respondents' according to the FP had higher levels of life satisfaction and net income, but performed less physical activities in comparison to high frail people according to the CFAI. CONCLUSION: The present study shows that the FP and CFAI partly measure the same 'frailty-construct', although differences were found for instance in the prevalence of frailty and the composition of the 'frail participants'. Since 'being frail' is an inclusion criterion in many studies, researchers must be aware that the choice of the frailty measurement has an impact on both the estimates of frailty prevalence and the characteristics of the selected sample.

Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay.

INTRODUCTION: Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins. METHODS: 4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid. RESULTS: A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization. DISCUSSION: The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.

Relational aspects of mastery for frail, older adults: The role of informal caregivers in the care process.

Frail, older care recipients are often thought of as individuals with a decreased mastery of everyday life skills. Various authors have proposed to acknowledge a relational dimension of mastery, defined as the ability to maintain control over one's life with the help of others. This study explores how frail, older adults experience relational aspects of mastery and the role of their informal caregivers in maintaining these aspects of mastery over the care process. Qualitative interviews (N = 121) were conducted in 2016 with potentially frail, community-dwelling older adults participating in the Detection, Support and Care for Older people: Prevention and Empowerment (D-SCOPE) project. A secondary analysis of 65 interviews reveals that, according to frail, older adults, informal caregivers contribute in various ways to the preservation of their mastery. This differs across the four elements of care: caring about (attentiveness), taking care of (responsibility), care-giving (competence), and care-receiving (responsiveness). However, in some cases, older adults experienced a loss of mastery; for example, when informal caregivers did not understand their care needs and did not involve them in the decision, organisation, and provision of care. A relational dimension of mastery needs to be acknowledged in frail, older care recipients since stimulating mastery is a crucial element for realising community care objectives and person-centred and integrated care.

Randomized controlled trial to evaluate a prevention program for frail community-dwelling older adults: a D-SCOPE protocol.

BACKGROUND: Frail community-dwelling older adults, whom might experience problems regarding physical, cognitive, psychological, social and environmental factors, are at risk for adverse outcomes such as disability, institutionalization and mortality. People in need of help do not always find their way to care and support services and are left undetected. The aim of the D-SCOPE project is to detect frail community-dwelling older adults who previously went unnoticed and to improve their access to care and support. Goal is to increase their frailty-balance, quality of life, meaning in life, life satisfaction, mastery, community inclusion and ageing well in place. METHODS/DESIGN: The study is a prospective, longitudinal randomized four-armed controlled trial with follow-up at 6 months. The study group aims to include 900 community-dwelling older adults aged 60 years and over from 3 municipalities in Flanders (Belgium). While selecting the study group, risk profiles for frailty will be taken into account. Participants will be randomly selected from the census records in each municipality. Data will be collected prospectively at baseline (T0) and at follow-up, 6 months after baseline (T1). At baseline, participants who are at least mild frail on one of the 5 domains of frailty (CFAI-plus) or feel frail based on the subjective assessment of frailty will be randomly assigned to (1) the study group or (2) the control group. A mixed method design with the inclusion of quantitative and qualitative data analyses will be used to evaluate the efficacy and experiences of the detection and prevention program on frailty. DISCUSSION: The study will contribute to an innovative vision concerning the organization of care and support, and a timely and accurate detection and support of community-dwelling older adults at risk for frailty. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov, on May 26, 2017, identifier: NCT03168204 .

[Apathy, depression and cognitive functioning in patients with MCI and dementia]. / De relatie tussen apathie, depressie en cognitief functioneren bij patiënten met MCI en dementie.

BACKGROUND: In dementia, apathy and depression are often seen as one disorder because of the many overlapping symptoms. However, for therapy a correct differentiation is essential. Moreover, apathy and depression are likely both associated with different cognitive deficits and progression of the disease. In this research we give an overview of cognitive domains associated with apathy and depression in MCI patients and report how often both disorders occur in a population sample. METHOD: We administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to 117 cognitively healthy controls (GC), 97 patients with mild cognitive impairment (MCI) and 50 patients with dementia (DEM). In addition, the Apathy Evaluation Scale clinical version (AES-C) and the Geriatric Depression Scale (GDS) were administered. RESULTS: The number of patients with apathy increased with cognitive decline with respectively 3.4%, 10.4% and 41.5% of patients in the GC, MCI and DEM group. The prevalence of isolated depression was highest in the MCI group (18.8%). Correlation analyses in the MCI group showed that apathy and not depression was associated with a deficit in encoding, attention and global cognitive functioning. CONCLUSION: The prevalence of apathy and depressive symptoms is different in patients with MCI, DEM and GC, and within the MCI group apathy and depression are associated with different cognitive domains.