Psychological outcomes of dementia risk estimation in MCI patients: Results from the PreDADQoL project.

INTRODUCTION: Understanding the impact of biomarker-based dementia risk estimation in people with mild cognitive impairment (MCI) and their care partners is critical for patient care. METHODS: MCI patients and study partners were counseled on Alzheimer's disease (AD) biomarker and dementia risk was disclosed. Data on mood, quality of life (QoL), and satisfaction with life (SwL) were obtained 1 week and 3 months after disclosure. RESULTS: Seventy-six dyads were enrolled, and two-thirds of the patients opted for biomarker testing. None of the participants experienced clinically relevant depression or anxiety after disclosure. All dyads reported moderate to high QoL and SwL throughout the study. Patients reported more subthreshold depressive symptoms 1 week and lower QoL and SwL 3 months after disclosure. In patients, depression (odds ratio [OR]: 0.76) and anxiety (OR: 0.81) were significant predictors for the decision against biomarker testing. DISCUSSION: No major psychological harm is to be expected in MCI patients and care partners after dementia risk disclosure. TRIAL REGISTRATION: This study is registered in the German clinical trials register (Deutsches Register Klinischer Studien, DRKS): http://www.drks.de/DRKS00011155, DRKS registration number: DRKS00011155, date of registration: 18.08.2017. HIGHLIGHTS: Patients with mild cognitive impairment (MCI) and study partners were counseled on Alzheimer's disease (AD) biomarker-based dementia risk estimation. About two-thirds of patients opted for biomarker testing and received their dementia risk based on their AD biomarker status. Patients who decided in favor or against CSF biomarker testing differed in psychological features. We did not observe major psychological harm after the dementia risk disclosure. Coping strategies were associated with better subsequent mood and well-being in all participants.

A randomized, open-label clinical trial in mild cognitive impairment with EGb 761 examining blood markers of inflammation and oxidative stress.

Although beta-amyloid (Aß) and phosphorylated tau remain the preferred targets for disease-modifying treatments (DMT) against Alzheimer's disease (AD), part of the pathophysiological mechanisms of cognitive impairment are related to neuroinflammation and oxidative stress. In mild cognitive impairment (MCI), a prodromal stage of AD and other neurodegenerative conditions, the joint appearance of inflammation, oxidative stress, and metabolic alterations are the common pathways of neurotoxicity and neurodegeneration. The standardized extract of Ginkgo biloba EGb 761 interferes with the pathogenic mechanisms involved in both the development of cognitive impairment due to AD and that of vascular origin. The primary objective of this study is to compare changes in the levels of blood markers of inflammation and oxidative stress after treatment with EGb 761 in a cohort of 100 patients with MCI. In addition, we aim to assess changes in these blood markers during an additional 12-month extension phase in which patients in the control group will also receive EGb 761 and patients in the active group will extend their treatment duration. Secondary objectives include comparing changes in neuropsychiatric and cognitive test scores between the baseline (v0) and 12-month visits (v2). This study is a Phase IV, single-center, randomized, open-label, parallel-group clinical trial consisting of the 12-month follow-up of a cohort of participants with MCI [Global Deterioration Scale (GDS) = 3] and an extension with an additional 12-month follow-up. During the first 12 months, participants will be randomized into two arms: in one arm, patients will receive 1 daily tablet of EGb 761 240 mg orally (study group, n = 50), while in the other arm, patients will not receive EGb 761 and will undergo the same assessments as the treated group (control group, n = 50). After the first 12 months of the study, patients in the EGb 761-treated group will continue treatment, and patients in the control group will be offered one EGb 761 240 mg tablet per day orally. All participants will be monitored for an additional 12 months. A battery of blood markers of inflammation and oxidative stress will be quantified at v0, v1, v2, v3, and v4. The Olink Proteomics panel of inflammation markers ( https://www.olink.com/products/inflammation/ ) will be used to evaluate 92 proteins associated with inflammatory diseases and related biological processes. The second panel measures 92 proteins involved in neurological processes. At v0, v2, and v4, neuropsychological and neurological evaluations will be conducted in addition to vital signs and anthropometric studies using a body composition monitor with bioimpedance technology (Tanita). Sixty percent of the 100 MCI patients recruited were women. The mean age was 73.1 years, and the mean time between symptom onset and MCI diagnosis was 2.9 years. The mean Mini-Mental State Examination (MMSE) score was 26.7. Depressive and anxiety disorders, as well as vascular risk factors, were the most frequent comorbidities among the cohort. The study is still ongoing, and results for the first year of treatment (v0, v1, v2) are expected by 2023. Individuals with MCI have an elevated risk of developing dementia. EGb 761 is used worldwide for the symptomatic treatment of cognitive disorders due to its neuroprotective effects. In experimental models and clinical observational studies, EGb 761 has shown strong antioxidant and anti-inflammatory activity. As a result, this study has been proposed to evaluate the antioxidant and anti-inflammatory effects on plasma markers and their potential clinical correlation with the progression of cognitive decline in patients with MCI.Trial registration: Registro Español de estudios clínicos (REec) number 2020-003776-41, ClinicalTrials.gov Identifier: NCT05594355.

Sex, Neuropsychiatric Profiles, and Caregiver Burden in Alzheimer's Disease Dementia: A Latent Class Analysis.

BACKGROUND: Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) can be disruptive for patients and their families. OBJECTIVE: We aimed to classify patients based on NPS and to explore the relationship of these classes with sex and with caregiver burden. METHODS: The study cohort comprised individuals with AD dementia diagnosed at Ace Alzheimer Center in Barcelona, Spain, between 2011-2020. NPS were ascertained by using the Neuropsychiatric Inventory-Questionnaire. Latent class analysis was used to identify clusters of individuals sharing a similar NPS profile. We evaluated the caregiver burden using the Zarit Burden Interview. Multivariable regression models were used to obtain adjusted estimates of the association between sex, NPS classes, and caregiver burden. RESULTS: A total of 1,065 patients with AD dementia and their primary caregivers were included. We classified patients into five different classes according to their NPS profile: "Affective", "High-behavioral-disturbance", "Negative-affect", "Affective/deliriant", and "Apathy". We found that age, sex, and type of AD diagnosis differed greatly across classes. We found that patients from the "High-behavioral-disturbance" (OR = 2.56, 95% CI: 1.00-6.56), "Negative-affect" (OR = 2.72, 95% CI: 1.26-3.64), and "Affective/deliriant" (OR = 2.14, 95% CI: 1.26-3.64) classes were over two times more likely to have a female caregiver than those in "Apathy" class. These three classes were also the ones associated to the greatest caregiver burden in the adjusted analyses, which seems to explain the increased burden observed among female caregivers. CONCLUSION: Caregiver burden is highly dependent on the patient's NPS profiles. Female caregivers provide care to patients that pose a greater burden, which makes them more susceptible to become overwhelmed.

Biomarker-Based Risk Prediction of Alzheimer's Disease Dementia in Mild Cognitive Impairment: Psychosocial, Ethical, and Legal Aspects.

BACKGROUND: Today, a growing number of individuals with mild cognitive impairment (MCI) wish to assess their risk of developing Alzheimer's disease (AD) dementia. The expectations as well as the effects on quality of life (QoL) in MCI patients and their close others through biomarker-based dementia risk estimation are not well studied. OBJECTIVE: The PreDADQoL project aims at providing empirical data on effects of such prediction on QoL and at developing an ethical and legal framework of biomarker-based dementia risk estimation in MCI. METHODS: In the empirical study, 100 MCI-patients and their close others will be recruited from two sites (Germany and Spain). They receive standardized counselling on cerebrospinal fluid (CSF) biomarker-based prediction of AD dementia and a risk disclosure based on their AD biomarker status. A mixed methods approach will be applied to assess outcomes. RESULTS: The pilot-study yielded a specification of the research topics and newly developed questionnaires for the main assessment. Within this binational quantitative and qualitative study, data on attitudes and expectations toward AD risk prediction, QoL, risk communication, coping strategies, mental health, lifestyle changes, and healthcare resource utilization will be obtained. Together with the normative part of the project, an empirically informed ethical and legal framework for biomarker-based dementia risk estimation will be developed. CONCLUSION: The empirical research of the PreDADQoL study together with the ethical and legal considerations and implications will help to improve the process of counselling and risk disclosure and thereby positively affect QoL and health of MCI-patients and their close others in the context of biomarker-based dementia risk estimation.

Dementia Care in Times of COVID-19: Experience at Fundació ACE in Barcelona, Spain.

BACKGROUND: Fundació ACE is a non-profit organization providing care based on a holistic model to persons with cognitive disorders and their families for 25 years in Barcelona, Spain. Delivering care to this vulnerable population amidst the COVID-19 pandemic has represented a major challenge to our institution. OBJECTIVE: To share our experience in adapting our model of care to the new situation to ensure continuity of care. METHODS: We detail the sequence of events and the actions taken within Fundació ACE to swiftly adapt our face-to-face model of care to one based on telemedicine consultations. We characterize individuals under follow-up by the Memory Unit from 2017 to 2019 and compare the number of weekly visits in 2020 performed before and after the lockdown was imposed. RESULTS: The total number of individuals being actively followed by Fundació ACE Memory Unit grew from 6,928 in 2017 to 8,147 in 2019. Among those newly diagnosed in 2019, most patients had mild cognitive impairment or mild dementia (42% and 25%, respectively). Weekly visits dropped by 60% following the suspension of face-to-face activity. However, by April 24 we were able to perform 78% of the visits we averaged in the weeks before confinement began. DISCUSSION: We have shown that Fundació ACE model of care has been able to successfully adapt to a health and social critical situation as COVID-19 pandemic. Overall, we were able to guarantee the continuity of care while preserving the safety of patients, families, and professionals. We also seized the opportunity to improve our model of care.

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project.

INTRODUCTION: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. METHODS: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. RESULTS: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. DISCUSSION: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.

Exploring Genetic Associations of Alzheimer's Disease Loci With Mild Cognitive Impairment Neurocognitive Endophenotypes.

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)" (ß = -0.76, p = 4.1 × 10-10), "learning" (ß = -1.35, p = 2.91 × 10-6), and "recognition memory" (ß = -0.58, p = 9.67 × 10-5); and with "DR" in the aMCI group (ß = -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 (ß = -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 (ß = 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" (ß = -0.19, p = 5.34 × 10-6). Overall, our findings support specific associations of established AD-associated SNPs with MCI NEs.

Patient Engagement: The Fundació ACE Framework for Improving Recruitment and Retention in Alzheimer's Disease Research.

Alzheimer's disease (AD) research is at a critical time. The global society is increasingly aware of the frightening rate of growth of the human and financial burden caused by this condition and of the urgent need to halt its progression. Consequently, the scientific community holds great responsibility to quickly put in place and optimize the machinery necessary for testing new treatments or interventions. In this context demand for participants for AD research is at an all-time high. In this review, we will focus on a methodological factor that is increasingly recognized as a key factor that shapes trial populations and affects validity of results in clinical trials: patient engagement, recruitment, and retention. We outline specific problems relevant to patient engagement in AD including recruiting enough participants, difficulties in participant retention, ensuring the recruited sample is representative of the general AD population, the burden of screening failures, and new challenges related to recruiting in preclinical disease. To address the urgent need for more research studying the applicability and cost-effectiveness of different recruitment strategies across different settings and nationalities, we describe the Models of Patient Engagement for Alzheimer's Disease (MOPEAD) project, a public-private partnership promoted by the Innovative Medicine Initiative (IMI), which will provide a large multinational quantitative analysis comparing different innovative recruitment models. We also discuss strategies that address each problem and draw on the experience of Fundació ACE to argue that focusing resources on comprehensive AD centers that offer coordinated clinical and social care and participate in basic and clinical research, is an effective and efficient way of implementing many of the discussed strategies.

Social Representation of Dementia: An Analysis of 5,792 Consecutive Cases Evaluated in a Memory Clinic.

BACKGROUND: Different interpretations of cognitive impairment and dementia due to differences in health structures, such as cultural differences could affect the diagnosis and treatment of the condition. it is reasonable to expect that the social and family impact of the disease and coping strategies will differ among societies. OBJECTIVE: The general aim of this study is to understand the social representations of dementia, its associated practices, and the effects they imply. METHODS: People diagnosed with clinical dementia and their families were assessed from 2005 to 2015 in the memory clinic of the Fundació ACE, Institut Català de Neurociències Aplicades in Barcelona, Spain. RESULTS: 9,898 people were examined and 5,792 were diagnosed with dementia. For those with a caregiver (71%), the decision-making fell on the person with dementia in 16.2% of the cases; and for those without a caregiver, in 26.4% of the cases the family did not perceive the deficits as a disease, which led to multiple risk situations (74.6%). CONCLUSIONS: The recognition of dementia as part of aging is common among families. Consequently, risk situations may arise and diagnosis and access to treatment may be delayed. The incorporation of a social appraisal to the diagnostic process is a necessity to evaluate these situations.

Beneficial Effects of an Integrated Psychostimulation Program in Patients with Alzheimer's Disease.

BACKGROUND: The existing pharmacological treatments for Alzheimer's disease (AD) can only slow the progression of symptoms or delay admission to long-term care facilities. The beneficial effects of non-drug treatments are poorly studied. OBJECTIVE: To describe the effects of an Integrated Psychostimulation Program (IPP) in patients with mild-moderate AD treated with acetylcholinesterase inhibitors; and to identify factors related to greater benefit of the IPP. METHODS: 206 patients (mean age = 75.9 years; MMSE = 19.6) were evaluated before starting the IPP and 3, 6, 9, and 12 months later. Measures included: Mini-Mental State Examination (MMSE), Cognitive Subscale of Alzheimer's Disease Assessment Scale (ADAS-Cog), Rapid Disability Rating Scale (RDRS-2), and Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS: Patients remained cognitively stable (MMSE/ADAS-Cog) for more than 6 months and significantly worsened at 9-month and 12-month follow-ups, without clinically significant functional changes (RDRS-2) or psychiatric symptoms(NPI-Q). The mean annual change on MMSE and ADAS-Cog were 2.06 and 3.56 points, respectively, lower than the annual decline demonstrated previously in similar patients (2.4 and 4.5, respectively). 42.7% of patients maintained or improved global cognitive scores between baseline and 12-month follow-up. The patients who maintained cognitive functions were older than those who did not (77.5 versus 74.7 years). CONCLUSIONS: The IPP may be an effective treatment to maintain cognition, functionality, and psychiatric symptoms in AD patients pharmacologically treated, and older age seems to increase beneficial effects of IPP.