Ellen Elisa De Roeck

A Decade of Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease in Belgium

During the past ten years, over 5,000 cerebrospinal fluid (CSF) samples were analyzed at the Reference Center for Biological Markers of Dementia (BIODEM), UAntwerp, for core Alzheimers disease (AD) CSF biomarkers: amyloid-β peptide of 42 amino acids (Aβ1-42), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181P). CSF biomarker analyses were performed using single-analyte ELISA kits. In-house validated cutoff values were applied: Aβ1-42 <638.5 pg/mL, T-tau >296.5 pg/mL, P-tau181P >56.5 pg/mL. A CSF biomarker profile was considered to be suggestive for AD if the CSF Aβ1-42 concentration was below the cutoff, in combination with T-tau and/or P-tau181P values above the cutoff (IWG2 criteria for AD). Biomarker analyses were requested for following clinical indications: 1) neurochemical confirmation of AD in case of clinical AD, 2) neurochemical confirmation of AD in case of doubt between AD and a non-AD dementia, 3) neurochemical diagnosis of prodromal AD in case of mild cognitive impairment, 4) neurochemical confirmation of AD in case of psychiatric symptoms (like depression, psychosis), or 5) other clinical indications. During these ten years, the number of yearly referred samples increased by 238% and clinical indications for referral showed a shift from neurochemical confirmation of AD in case of clinical AD to differential dementia diagnosis in case of doubt between AD and a non-AD dementia. Four percent of the patients also had a postmortem neuropathological examination. Together, these biomarker data were the basis for several research papers, and significantly contributed to the validation of these biomarkers in autopsy-confirmed subjects.

The Cerebrospinal Fluid Neurogranin/BACE1 Ratio is a Potential Correlate of Cognitive Decline in Alzheimer's Disease.

Background: In diagnosing Alzheimer’s disease (AD), ratios of cerebrospinal fluid (CSF) biomarkers, such as CSF Aβ1-42/tau, have an improved diagnostic performance compared to the single analytes, yet, still a limited value to predict cognitive decline. Since synaptic dysfunction/loss is closely linked to cognitive impairment, synaptic proteins are investigated as candidate CSF AD progression markers. Objective: We studied CSF levels of the postsynaptic protein neurogranin and protein BACE1, predominantly localized presynaptically, and their relation to CSF total-tau, Aβ1-42, Aβ1-40, and Aβ1-38. All six analytes were considered as single parameters as well as ratios. Methods: Every ELISA involved was based on monoclonal antibodies, including the BACE1 and neurogranin immunoassay. The latter specifically targets neurogranin C-terminally truncated at P75, a more abundant species of the protein in CSF. We studied patients with MCI due to AD (n = 38) and 50 dementia due to AD patients, as well as age-matched cognitively healthy elderly (n = 20). A significant subset of the patients was followed up by clinical and neuropsychologically (MMSE) examinations for at least one year. Results: The single analytes showed statistically significant differences between the clinical groups, but the ratios of analytes indeed had a higher diagnostic performance. Furthermore, only the ratio of CSF neurogranin trunc P75/BACE1 was significantly correlated with the yearly decline in MMSE scores in patients with MCI and dementia due to AD, pointing toward the prognostic value of the ratio. Conclusion: This is the first study demonstrating that the CSF neurogranin trunc P75/BACE1 ratio, reflecting postsynaptic/presynaptic integrity, is related to cognitive decline.

Identifying frailty risk profiles of home-dwelling older people: focus on sociodemographic and socioeconomic characteristics

Abstract Objectives: This paper investigates risk profiles of frailty among older people, as these are essential for detecting those individuals at risk for adverse outcomes and to undertake specific preventive actions. Frailty is not only a physical problem, but also refers to emotional, social, and environmental hazards. Methods: Using data generated from the Belgian Ageing Studies, a cross-sectional study (n = 28,049), we tested a multivariate regression model that included sociodemographic and socioeconomic indicators as well as four dimensions of frailty, for men and women separately. Results: The findings indicated that for both men and women, increased age, having no partner, having moved house in the previous 10 years, having a lower educational level and having a lower household income are risk characteristics for frailty. Moreover, when looking at the different frailty domains, different risk profiles arose, and gender-specific risk characteristics were detected. Discussion: This paper elaborates on practical implications, and formulates a number of future research recommendations to tackle frailty in an aging society. The conclusion demonstrates the necessity for a thorough knowledge of risk profiles of frailty, as this will save both time and money and permit preventive actions to be more individually tailored.

The frequency and influence of dementia risk factors in prodromal Alzheimer's disease

We investigated whether dementia risk factors were associated with prodromal Alzheimers disease (AD) according to the International Working Group-2 and National Institute of Aging-Alzheimers Association criteria, and with cognitive decline. A total of 1394 subjects with mild cognitive impairment from 14 different studies were classified according to these research criteria, based on cognitive performance and biomarkers. We compared the frequency of 10 risk factors between the subgroups, and used Cox-regression to examine the effect of risk factors on cognitive decline. Depression, obesity, and hypercholesterolemia occurred more often in individuals with low-AD-likelihood, compared with those with a high-AD-likelihood. Only alcohol use increased the risk of cognitive decline, regardless of AD pathology. These results suggest that traditional risk factors for AD are not associated with prodromal AD or with progression to dementia, among subjects with mild cognitive impairment. Future studies should validate these findings and determine whether risk factors might be of influence at an earlier stage (i.e., preclinical) of AD.

The Cerebrospinal Fluid Aβ1–42/Aβ1–40 Ratio Improves Concordance with Amyloid-PET for Diagnosing Alzheimer’s Disease in a Clinical Setting

Background: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-β (Aβ) increases when the CSF Aβ1–42/Aβ1–40 ratio is used as compared to CSF Aβ1–42 levels alone. Objective: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer’s disease (AD) in a clinical setting. Methods: Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [18F]Florbetapir ([18F]AV45) PET scan, [18F]FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (Aβ1–42, Aβ1–40, T-tau, P-tau181). Results: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [18F]AV45 PET measures when the CSF Aβ1–42/Aβ1–40 was applied compared to Aβ1–42 alone. CSF biomarkers were stronger associated to [18F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matter Conclusions: The concordance between CSF Aβ and [18F]AV45 PET increases when the CSF Aβ1–42/Aβ1–40 ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD.

Next Generation Brain Health Depends on Early Alzheimer Disease Diagnosis: From a Timely Diagnosis to Future Population Screening

changes with the progression of dementia. 10 Educating caregivers on the importance of attentive listening, respect, and consideration of the turmoil inside the mind of an elderly person may help to improve the outcome of early detection of elderly individuals with cognitive decline. Finally, a nationwide clinical registry of dementia has been introduced in Japan, called the Organized Registration for the Assessment of dementia on Nationwide General consortium toward Effective treatment (ORANGE), which consists of multiple registries stratified by clinical stage: preclinical, prodromal, early, and advanced stage dementia. Individuals will be examined in a super-longitudinal fashion, and their genetic risks, lifestyle, mental state, social background, and care process will be assessed. It is expected to accelerate early detection of persons with cognitive decline and to provide a new model of prevention and care of dementia in the super-aged society. References 1. Alzheimer’s Association. 2015 Alzheimer’s disease facts and figures. Alzheimers

CFAI-Plus: Adding cognitive frailty as a new domain to the comprehensive frailty assessment instrument

Cognitive frailty is characterized by the presence of cognitive impairment in exclusion of dementia. In line with other frailty domains, cognitive frailty is associated with negative outcomes. The Comprehensive Frailty Assessment Instrument (CFAI) measures 4 domains of frailty, namely physical, psychological, social, and environmental frailty. The absence of cognitive frailty is a limitation.

Detecting frail, older adults and identifying their strengths: results of a mixed-methods study

BackgroundThe debate on frailty in later life focuses primarily on deficits and their associations with adverse (health) outcomes. In addition to deficits, it may also be important to consider the abilities and resources of older adults. This study was designed to gain insights into the lived experiences of frailty among older adults to determine which strengths can balance the deficits that affect frailty.MethodsData from 121 potentially frail community-dwelling older adults in Flemish-speaking Region of Belgium and Brussels were collected using a mixed-methods approach. Quantitative data were collected using the Comprehensive Frailty Assessment Instrument (CFAI), Montreal Cognitive Assessment (MoCA), and numeric rating scales (NRS) for quality of life (QoL), care and support, meaning in life, and mastery. Bivariate analyses, paired samples t-tests and means were performed. Qualitative data on experiences of frailty, frailty balance, QoL, care and support, meaning in life, and mastery were collected using semi-structured interviews. Interviews were subjected to thematic content analysis.ResultsThe “no to mild frailty” group had higher QoL, care and support, meaning in life, and mastery scores than the “severe frailty” group. Nevertheless, qualitative results indicate that, despite being classified as frail, many older adults experienced high levels of QoL, care and support, meaning in life, and mastery. Respondents mentioned multiple balancing factors for frailty, comprising individual-level circumstances (e.g., personality traits, coping strategies, resilience), environmental influences (e.g., caregivers, neighborhood, social participation), and macro-level features (e.g., health literacy, adequate financial compensation). Respondents also highlighted that life changes affected their frailty balance, including changes in health, finances, personal relationships, and living situation.ConclusionThe findings indicate that frailty among older individuals can be considered as a dynamic state and, regardless of frailty, balancing factors are important in maintaining a good QoL. The study investigated not only the deficits, but also the abilities, and resources of frail, older adults. Public policymakers and healthcare organizations are encouraged to include these abilities, supplementary or even complementary to the usual focus on deficits.

BLOOD FLOW–INDEPENDENT QUANTIFICATION OF [18F]-AV45 PET USING MODEL-BASED KINETICS WITH A METABOLITE-CORRECTED ARTERIAL INPUT FUNCTION

tex yielded a 0.664 AUC to distinguish between MCI converters and non-converters. Of the available regions from the FreeSurfer atlas, the Right Inferior Temporal was the most sensitive (AUC 1⁄4 0.698). Results for the next best other individual regions are shown in Table 2. The Lasso method selected a composite region made of 15 subregions (see Table 1), showing marginally higher sensitivity (AUC 1⁄4 0.700). Conclusions:While a regional analysis of cortical thickness best predicts conversion to AD, compared towhole cortex analysis, looking for an optimal aggregation did not provide significantly better results. Nevertheless, such approach may be more robust to image quality issues, which is to be further confirmed on other datasets. A similar analysis will be performed on longitudinal data in order to determine which single or composite region would provide the best effect size when measuring change in cortical thickness over time.