| 1. |
- Alanko, V, et al.
(författare)
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Mechanisms Underlying Non-Pharmacological Dementia Prevention Strategies: A Translational Perspective
- 2022
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Ingår i: The journal of prevention of Alzheimer's disease. - : SERDI. - 2426-0266 .- 2274-5807. ; 9:1, s. 3-11
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Tidskriftsartikel (refereegranskat)abstract
- Since developing an effective treatment for Alzheimer’s disease (AD) has been encountered as a challenging task, attempts to prevent cognitive decline by lifestyle modifications have become increasingly appealing. Physical exercise, healthy diet, and cognitive training are all modifiable, non-pharmacological lifestyle factors considered to influence cognitive health. Implementing lifestyle modifications on animal models of AD and cognitive impairment may reveal underlying mechanisms of action by which healthy lifestyle contribute to brain health. In mice, different types of lifestyle interventions have been shown to improve cognitive abilities, alleviate AD-related pathology and neuroinflammation, restore mitochondrial function, and have a positive impact on neurogenesis and cell survival. Different proteins and pathways have been identified to mediate some of the responses, amongst them BDNF, Akt–GSK3β, JNK, and ROCK pathway. Although some important pathways have been identified as mediating improvements in brain health, more research is needed to confirm these mechanisms of action and to improve the understanding of their interplay. Moreover, multidomain lifestyle interventions targeting multiple risk factors simultaneously may be a promising avenue in future dementia prevention strategies. Therefore, future work is needed to better understand the synergistic impact of combinatory lifestyle strategies on cellular mechanisms and brain health.
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| 2. |
- Bateman, R J, et al.
(författare)
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Plasma Biomarkers of AD Emerging as Essential Tools for Drug Development: An EU/US CTAD Task Force Report.
- 2019
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Ingår i: The journal of prevention of Alzheimer's disease. - : SERDI. - 2426-0266 .- 2274-5807. ; 6:3, s. 169-173
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Tidskriftsartikel (refereegranskat)abstract
- There is an urgent need to develop reliable and sensitive blood-based biomarkers of Alzheimer's disease (AD) that can be used for screening and to increase the efficiency of clinical trials. The European Union-North American Clinical Trials in Alzheimer's Disease Task Force (EU/US CTAD Task Force) discussed the current status of blood-based AD biomarker development at its 2018 annual meeting in Barcelona, Spain. Recent improvements in technologies to assess plasma levels of amyloid beta indicate that a single sample of blood could provide an accurate estimate of brain amyloid positivity. Plasma neurofilament light protein appears to provide a good marker of neurodegeneration, although not specific for AD. Plasma tau shows some promising results but weak or no correlation with CSF tau levels, which may reflect rapid clearance of tau in the bloodstream. Blood samples analyzed using -omics and other approaches are also in development and may provide important insight into disease mechanisms as well as biomarker profiles for disease prediction. To advance these technologies, international multidisciplinary, multi-stakeholder collaboration is essential.
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| 3. |
- Bloniecki, V, et al.
(författare)
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Digital Screening for Cognitive Impairment - A Proof of Concept Study
- 2021
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Ingår i: The journal of prevention of Alzheimer's disease. - : SERDI. - 2426-0266 .- 2274-5807. ; 8:2, s. 127-134
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Tidskriftsartikel (refereegranskat)abstract
- Background: Due to an ageing demographic and rapid increase of cognitive impairment and dementia, combined with potential disease-modifying drugs and other interventions in the pipeline, there is a need for the development of accurate, accessible and efficient cognitive screening instruments, focused on early-stage detection of neurodegenerative disorders. Objective: In this proof of concept report, we examine the validity of a newly developed digital cognitive test, the Geras Solutions Cognitive Test (GCST) and compare its accuracy against the Montreal Cognitive Assessment (MoCA). Methods: 106 patients, referred to the memory clinic, Karolinska University Hospital, due to memory complaints were included. All patients were assessed for presence of neurodegenerative disorder in accordance with standard investigative procedures. 66% were diagnosed with subjective cognitive impairment (SCI), 25% with mild cognitive impairment (MCI) and 9% fulfilled criteria for dementia. All patients were administered both MoCA and GSCT. Descriptive statistics and specificity, sensitivity and ROC curves were established for both test. Results: Mean score differed significantly between all diagnostic subgroups for both GSCT and MoCA (p<0.05). GSCT total test time differed significantly between all diagnostic subgroups (p<0.05). Overall, MoCA showed a sensitivity of 0.88 and specificity of 0.54 at a cut-off of <=26 while GSCT displayed 0.91 and 0.55 in sensitivity and specificity respectively at a cut-off of <=45. Conclusion: This report suggests that GSCT is a viable cognitive screening instrument for both MCI and dementia.
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| 4. |
- Bloniecki, Victor, et al.
(författare)
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The Geras Solutions Cognitive Test for Assessing Cognitive Impairment : Normative Data from a Population-Based Cohort
- 2023
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Ingår i: The Journal of Prevention of Alzheimer's Disease. - : Springer. - 2274-5807 .- 2426-0266. ; 2:10, s. 207-211
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is a need for the development of accurate, accessible and efficient screening instruments, focused on early-stage detection of neurocognitive disorders. The Geras Solutions cognitive test (GSCT) has showed potential as a digital screening tool for cognitive impairment but normative data are needed.Objective: The aim of this study was to obtain normative data for the GSCT in cognitively healthy patients, investigate the effects of gender and education on test scores as well as examine test-retest reliability.Methods: The population in this study consisted of 144 cognitively healthy subjects (MMSE>26) all at the age of 70 who were earlier included in the Healthy Aging Initiative Study conducted in Umea, Sweden. All patients conducted the GSCT and a subset of patients (n=32) completed the test twice in order to establish test-retest reliability.Results: The mean GSCT score was 46.0 (+/- 4.5) points. High level of education (>12 years) was associated with a high GSCT score (p = 0.02) while gender was not associated with GSCT outcomes (p = 0.5). GSCT displayed a high correlation between test and retest (r(30) = 0.8, p <0.01).Conclusion: This study provides valuable information regarding normative test-scores on the GSCT for cognitively healthy individuals and indicates education level as the most important predictor of test outcome. Additionally, the GSCT appears to display a good test-retest reliability further strengthening the validity of the test.
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| 5. |
- Chan, S-P, et al.
(författare)
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Associations of Long-Term Tea Consumption with Depressive and Anxiety Symptoms in Community-Living Elderly : Findings from the Diet and Healthy Aging Study
- 2018
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Ingår i: The Journal of Prevention of Alzheimer's Disease. - : SERDI. - 2274-5807 .- 2426-0266. ; 5:1, s. 21-25
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine the association between long-term tea consumption and depressive and anxiety symptoms in community-living elderly. DESTGN: Community based cross-sectional study. SETTING: The Diet and Healthy Aging Study (DaHA), a prospective cohort study in Singapore. PARTICIPANTS: 614 elderly aged 60 years and above, who were free of dementia and cognitive impairment. MEASUREMENTS: Information on tea consumption was obtained through interviewer-administered questionnaire. Long-term tea drinking was defined as regular consumption for at least 15 years. Depressive and anxiety symptoms were measured using the 15-item Geriatric Depression Scale (GDS-15) and the 20-item Geriatric Anxiety Inventory (GAI), respectively. A generalized structural equation model (gSEM) was applied to ascertain the association between long-term tea consumption and depressive and anxiety symptoms. RESULTS: About 59% of the subjects had consumed tea for over 15 years. Long term tea consumption was significantly associated with a reduced odds of having depressive and anxiety symptoms, after adjusting for demographics (i.e., age, gender, education and ethnicity), comorbid conditions (i.e., heart disease, diabetes, stroke, hypertension and hyperlipidaemia) and long-term coffee consumption. CONCLUSION: There was evidence suggesting that long-term tea consumption was associated with reduced depressive and anxiety symptoms among community-living elderly. This suggests that it is worthwhile to further investigate the role of tea's bioactive compounds in promoting mental health in aging.
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| 6. |
- Chertkow, H., et al.
(författare)
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An Action Plan to Face the Challenge of Dementia : INTERNATIONAL STATEMENT ON DEMENTIA from IAP for Health
- 2018
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Ingår i: The Journal of Prevention of Alzheimer's Disease. - : EDITIONS SERDI. - 2274-5807 .- 2426-0266. ; 5:3, s. 207-212
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Tidskriftsartikel (refereegranskat)abstract
- An international committee set up through the IAP for Health met to develop an action plan for dementia. Comprehensive international and national initiatives should move forward with calls for action that include increased public awareness regarding brain health and dementia, support for a broad range of dementia research objectives, and investment in national health care systems to ensure timely competent person-centred care for individuals with dementia. The elements of such action plans should include: 1) Development of national plans including assessment of relevant lifecourse risk and protective factors; 2) Increased investments in national research programs on dementia with approximately 1% of the national annual cost of the disease invested; 3) Allocating funds to support a broad range of biomedical, clinical, and health service and systems research; 4) Institution of risk reduction strategies; 5) Building the required trained workforce (health care workers, teachers, and others) to deal with the dementia crisis; 6) Ensuring that it is possible to live well with dementia; and 7) Ensuring that all have access to prevention programs, care, and supportive living environments.
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| 7. |
- Cummings, J, et al.
(författare)
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Anti-Tau Trials for Alzheimer's Disease: A Report from the EU/US/CTAD Task Force.
- 2019
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Ingår i: The journal of prevention of Alzheimer's disease. - : SERDI. - 2426-0266 .- 2274-5807. ; 6:3, s. 157-163
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Tidskriftsartikel (refereegranskat)abstract
- Efforts to develop effective disease-modifying treatments for Alzheimer's disease (AD) have mostly targeted the amyloid β (Aβ) protein; however, there has recently been increased interest in other targets including phosphorylated tau and other forms of tau. Aggregated tau appears to spread in a characteristic pattern throughout the brain and is thought to drive neurodegeneration. Both neuropathological and imaging studies indicate that tau first appears in the entorhinal cortex and then spreads to the neocortex. Anti-tau therapies currently in Phase 1 or 2 trials include passive and active immunotherapies designed to prevent aggregation, seeding, and spreading, as well as small molecules that modulate tau metabolism and function. EU/US/CTAD Task Force members support advancing the development of anti-tau therapies, which will require novel imaging agents and biomarkers, a deeper understanding of tau biology and the dynamic interaction of tau and Aβ protein, and development of multiple targets and candidate agents addressing the tauopathy of AD. Incorporating tau biomarkers in AD clinical trials will provide additional knowledge about the potential to treat AD by targeting tau.
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| 8. |
- Fang, C., et al.
(författare)
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Buntanetap, a Novel Translational Inhibitor of Multiple Neurotoxic Proteins, Proves to Be Safe and Promising in Both Alzheimer’s and Parkinson’s Patients
- 2023
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Ingår i: Journal of Prevention of Alzheimer's Disease. - : SERDI. - 2274-5807 .- 2426-0266. ; 10:1, s. 25-33
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previously we reported the clinical safety and pharmacological activity of buntanetap (known as Posiphen or ANVS401) in healthy volunteers and mild cognitive impaired (MCI) patients (21). The data supported continued clinical evaluation of buntanetap for treating Alzheimer’s Disease (AD). Neurodegenerative diseases such as AD and Parkinson’s disease (PD) share several pathological manifestations, including increased levels of multiple neurotoxic protein aggregates. Therefore, a treatment strategy that targets toxic species common to both disorders can potentially provide better clinical outcomes than attacking one neurotoxic protein alone. To test this hypothesis, we recently completed a clinical study in early AD and early PD participants and report the data here. Objectives: We evaluated safety, pharmacokinetics, biomarkers, and efficacy of buntanetap in treating early AD and PD patients. Design: Double-blind, placebo-controlled, multi-center study. Setting: 13 sites in the US participated in this clinical trial. The registration number is NCT04524351 at ClinicalTrials.gov. Participants: 14 early AD patients and 54 early PD patients. Intervention: AD patients were given either 80mg buntanetap or placebo QD. PD patients were given 5mg, 10mg, 20mg, 40mg, 80mg buntanetap or placebo QD. Measurements: Primary endpoint is safety and tolerability; secondary endpoint is pharmacokinetics of buntanetap in plasma; exploratory endpoints are 1) biomarkers in cerebrospinal fluid (CSF) in both AD and PD patients 2) psychometric tests specific for AD (ADAS-Cogs & WAIS coding test) or PD (MDS-UPDRS & WAIS coding test). Results: Buntanetap was safe and well tolerated. Biomarker data indicated a trend in lowering levels of neurotoxic proteins and inflammatory factors and improving axonal integrity and synaptic function in both AD and PD cohorts. Psychometric tests showed statistically significant improvements in ADAS-Cog11 and WAIS coding in AD patients and MDS-UPDRS and WAIS coding in PD patients. Conclusions: Buntanetap is well tolerated and safe at doses up to 80mg QD in both AD and PD patients. Cmax and AUC increase with dose without evidence for a plateau up to 80mg QD. The drug shows promising evidence in exploratory biomarker and efficacy measures. Further evaluation of buntanetap in larger, longer-term clinical trials for the treatment of AD and PD are warranted. © 2022, The Authors.
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| 9. |
- Graf, A, et al.
(författare)
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Assessment of Clinical Meaningfulness of Endpoints in the Generation Program by the Insights to Model Alzheimer's Progression in Real Life (iMAP) Study
- 2019
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Ingår i: The journal of prevention of Alzheimer's disease. - : SERDI. - 2426-0266 .- 2274-5807. ; 6:2, s. 85-89
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Tidskriftsartikel (refereegranskat)abstract
- We are launching the Insights to Model Alzheimer’s Progression in Real Life study in parallel with the Alzheimer Prevention Initiative Generation Program. This is a 5-year, multinational, prospective, longitudinal, non-interventional cohort study that will collect data across the spectrum of Alzheimer’s disease. The primary objective is to assess the ability of the Alzheimer’s Prevention Initiative Cognitive Composite Test Score and Repeatable Battery for the Assessment of Neuropsychological Status to predict clinically meaningful outcomes such as diagnosis of mild cognitive impairment or dementia due to Alzheimer’s disease, and change in Clinical Dementia Rating – Global Score. This study is the first large-scale, prospective effort to establish the clinical meaningfulness of cognitive test scores that track longitudinal decline in preclinical Alzheimer’s disease. This study is also expected to contribute to our understanding of the relationships among outcomes in different stages of Alzheimer’s disease as well as models of individual trajectories during the course of the disease.
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| 10. |
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| 11. |
- Hendrix, S. B., et al.
(författare)
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Alzheimer's Disease Composite Score: a Post-Hoc Analysis Using Data from the LipiDiDiet Trial in Prodromal Alzheimer's Disease
- 2019
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Ingår i: Jpad-Journal of Prevention of Alzheimers Disease. - : SERDI. - 2274-5807 .- 2426-0266. ; 6:4, s. 232-236
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Tidskriftsartikel (refereegranskat)abstract
- As research evolves in prodromal AD, the need to validate sufficiently sensitive outcome measures, e.g. the Alzheimer's Disease Composite Score (ADCOMS) is clear. In the LipiDiDiet randomized trial in prodromal AD, cognitive decline in the study population was much less than expected in the timeframe studied. While the primary composite endpoint was insufficiently sensitive to detect a difference in the modified intention to treat population, the per-protocol population showed less decline in the active than the control group, indicating better treatment effects with regular product intake. These results were further strengthened by significant benefits on secondary endpoints of cognition and function, and brain atrophy. The present post-hoc analysis investigated whether ADCOMS could detect a difference between groups in the LipiDiDiet population (138 active, 140 control). The estimated mean change in ADCOMS from baseline (standard error) was 0.085 (0.018) in the active and 0.133 (0.018) in the control group; estimated mean treatment difference -0.048 (95% confidence intervals -0.090, -0.007; p=0.023), or 36% less decline in the active group. This suggests ADCOMS identified the cognitive and functional benefits observed previously, confirming the sensitivity of this composite measure.
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| 12. |
- Hendrix, S. B., et al.
(författare)
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Combined Evidence for a Long-Term, Clinical Slowing Effect of Multinutrient Intervention in Prodromal Alzheimer's Disease: Post-Hoc Analysis of 3-Year Data from the LipiDiDiet Trial
- 2023
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Ingår i: Jpad-Journal of Prevention of Alzheimers Disease. - : SERDI. - 2274-5807 .- 2426-0266. ; 10:3, s. 464-70
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Tidskriftsartikel (refereegranskat)abstract
- The LipiDiDiet randomized clinical trial is evaluating the long term effects of a multinutrient intervention (Fortasyn Connect) compared with control in participants with prodromal AD. In this post-hoc analysis we used the Alzheimer's Disease Composite Score (ADCOMS) as a measure of cognition and global function, together with a global statistical test (GST) and Bayesian hierarchical modelling (BHM) to evaluate the totality of evidence for an effect of the intervention over 36 months. The analysis includes 67 participants (39 active, 28 control) with change from baseline data after 36 months intervention. All outcome measures showed a statistically significant effect for the intervention: ADCOMS (P =0.045), GST (P <0.001), and BHM (P =0.008 based on 3 outcomes and P <0.001 including all primary and secondary quantitative clinical outcomes). Fortasyn Connect was associated with significantly less clinical decline over 36 months, suggesting the long-lasting beneficial effects of the multinutrient in prodromal AD.
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| 13. |
- Kootar, S., et al.
(författare)
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Validation of the CogDrisk Instrument as Predictive of Dementia in Four General Community-Dwelling Populations
- 2023
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Ingår i: The Journal of Prevention of Alzheimer's Disease. - : SERDI. - 2274-5807 .- 2426-0266. ; :10, s. 478-487
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lack of external validation of dementia risk tools is a major limitation for generalizability and translatability of prediction scores in clinical practice and research.Objectives: We aimed to validate a new dementia prediction risk tool called CogDrisk and a version, CogDrisk-AD for predicting Alzheimer’s disease (AD) using cohort studies.Design, Setting, Participants and Measurements: Four cohort studies were identified that included majority of the dementia risk factors from the CogDrisk tool. Participants who were free of dementia at baseline were included. The predictors were component variables in the CogDrisk tool that include self-reported demographics, medical risk factors and lifestyle habits. Risk scores for Any Dementia and AD were computed and Area Under the Curve (AUC) was assessed. To examine modifiable risk factors for dementia, the CogDrisk tool was tested by excluding age and sex estimates from the model.Results: The performance of the tool varied between studies. The overall AUC and 95% CI for predicting dementia was 0.77 (0.57, 0.97) for the Swedish National study on Aging and Care in Kungsholmen, 0.76 (0.70, 0.83) for the Health and Retirement Study - Aging, Demographics and Memory Study, 0.70 (0.67,0.72) for the Cardiovascular Health Study Cognition Study, and 0.66 (0.62,0.70) for the Rush Memory and Aging Project.Conclusions: The CogDrisk and CogDrisk-AD performed well in the four studies. Overall, this tool can be used to assess individualized risk factors of dementia and AD in various population settings.
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| 14. |
- Malzbender, K., et al.
(författare)
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Validation, Deployment, and Real-World Implementation of a Modular Toolbox for Alzheimer’s Disease Detection and Dementia Risk Reduction: The AD-RIDDLE Project
- 2024
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Ingår i: Journal of Prevention of Alzheimer's Disease. - 2274-5807 .- 2426-0266. ; 11:2, s. 329-338
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Tidskriftsartikel (refereegranskat)abstract
- The Real-World Implementation, Deployment, and Validation of Early Detection Tools and Lifestyle Enhancement (AD-RIDDLE) project, recently launched with the support of the EU Innovative Health Initiative (IHI) public-private partnership and UK Research and Innovation (UKRI), aims to develop, test, and deploy a modular toolbox platform that can reduce existing barriers to the timely detection, and therapeutic approaches in Alzheimer’s disease (AD), thus accelerating AD innovation. By focusing on health system and health worker practices, AD-RIDDLE seeks to improve and smooth AD management at and between each key step of the clinical pathway and across the disease continuum, from at-risk asymptomatic stages to early symptomatic ones. This includes innovation and improvement in AD awareness, risk reduction and prevention, detection, diagnosis, and intervention. The 24 partners in the AD-RIDDLE interdisciplinary consortium will develop and test the AD-RIDDLE toolbox platform and its components individually and in combination in six European countries. Expected results from this cross-sectoral research collaboration include tools for earlier detection and accurate diagnosis; validated, novel digital cognitive and blood-based biomarkers; and improved access to individualized preventative interventions (including multimodal interventions and symptomatic/disease-modifying therapies) across diverse populations, within the framework of precision medicine. Overall, AD-RIDDLE toolbox platform will advance management of AD, improving outcomes for patients and their families, and reducing costs.
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| 15. |
- Mattke, S., et al.
(författare)
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Estimates of Current Capacity for Diagnosing Alzheimer's Disease in Sweden and the Need to Expand Specialist Numbers
- 2024
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Ingår i: JPAD-JOURNAL OF PREVENTION OF ALZHEIMERS DISEASE. - 2274-5807 .- 2426-0266. ; 11:1, s. 155-161
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe emergence of disease-modifying Alzheimer's (AD) treatments provides new hope to patients and families but concerns have been raised about the preparedness of healthcare systems to provide timely access to such treatments because of a combination of a complex diagnostic process and a large prevalent pool.ObjectivesWe assess the preparedness of Sweden, a high-income country known for its dementia-friendly policies, to diagnose AD patients eligible for treatment within a six-month window, given current capacity for specialist evaluations and biomarker testing. We calculate the investment requirements for Sweden to achieve this target over a timeframe of 20 years.DesignDesk research to identify data for population, mortality, disease burden, cost of services and current capacity, expert consultation to inform assumptions about patient journey, and use of a Markov model to predict waiting times. The model simulates the patients' journey through different evaluation stages: initial evaluation by a primary care specialist, neurocognitive testing by an AD specialist, and confirmatory biomarker testing with PET scanning or cerebrospinal fluid (CSF) testing. The model assumes specialist appointments and PET scans are capacity constrained, and patients progress from cognitively normal to MCI and from MCI to dementia in the resulting waiting times.MeasurementsProjected waiting times for diagnosis of eligibility for disease-modifying Alzheimer's treatment from 2023 to 2042 assuming current capacity, assuming 20% of Swedish residents aged 60 years and above would seek an evaluation for cognitive decline. Investments required to scale capacity up to reach target of providing diagnosis within six months on average.ResultsInitial average waiting times for AD specialist appointments would be around 21 months in 2023 and remain around 55 months through 2042, as demand would continue to outstrip supply throughout the 20-year model horizon. Waiting times for biomarker testing would be stable at less than four weeks, as patients would be held up in the queue for their first specialist consultations, and use of CSF testing is widely accepted in Sweden. An additional 25% of AD specialists would have to be added above the current growth trend to reduce waiting times to less than 6 months at an average annual cost of approximately 805 million SEK. The increased cost of volume of biomarker testing would amount to about 106 million SEK per year.ConclusionsAt current capacity, the Swedish healthcare system is unable to provide timely diagnosis of patients eligible for disease-modifying AD treatment. Although future diagnostic technologies, such as digital cognitive assessments and blood tests for the AD pathology, might decrease demand for capacity-constrained services, substantial investments will be required to meet a target of less than six months of waiting time for a diagnosis.
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| 16. |
- Perez-Grijalba, V, et al.
(författare)
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Plasma Aβ42/40 Ratio Detects Early Stages of Alzheimer's Disease and Correlates with CSF and Neuroimaging Biomarkers in the AB255 Study
- 2019
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Ingår i: The journal of prevention of Alzheimer's disease. - : SERDI. - 2426-0266 .- 2274-5807. ; 6:1, s. 34-41
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Tidskriftsartikel (refereegranskat)abstract
- Background: Easily accessible biomarkers are needed for the early identification of individuals at risk of developing Alzheimer’s disease (AD) in large population screening strategies. Objectives: This study evaluated the potential of plasma β-amyloid (Aβ) biomarkers in identifying early stages of AD and predicting cognitive decline over the following two years. Design: Total plasma Aβ42/40 ratio (TP42/40) was determined in 83 cognitively normal individuals (CN) and 145 subjects with amnestic mild cognitive impairment (a-MCI) stratified by an FDG-PET AD-risk pattern. Results: Significant lower TP42/40 ratio was found in a-MCI patients compared to CN. Moreover, a-MCIs with a high-risk FDG-PET pattern for AD showed even lower plasma ratio levels. Low TP42/40 at baseline increased the risk of progression to dementia by 70%. Furthermore, TP42/40 was inversely associated with neocortical amyloid deposition (measured with PiB-PET) and was concordant with the AD biomarker profile in cerebrospinal fluid (CSF). Conclusions: TP42/40 demonstrated value in the identification of individuals suffering a-MCI, in the prediction of progression to dementia, and in the detection of underlying AD pathology revealed by FDG-PET, Amyloid-PET and CSF biomarkers, being, thus, consistently associated with all the well-established indicators of AD.
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| 17. |
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| 18. |
- Ritchie, CW, et al.
(författare)
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The European Prevention of Alzheimer's Dementia (EPAD) Longitudinal Cohort Study: Baseline Data Release V500.0
- 2020
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Ingår i: The journal of prevention of Alzheimer's disease. - : SERDI. - 2426-0266 .- 2274-5807. ; 7:1, s. 8-13
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Tidskriftsartikel (refereegranskat)abstract
- Background: The European Prevention of Alzheimer’s Dementia (EPAD) Programme is a pan-European project whose objective is to deliver a platform, adaptive, Phase 2 proof of concept (PoC) trial for the secondary prevention of Alzheimer’s dementia. A component of this platform is the Longitudinal Cohort Study (LCS) which acts as a readiness cohort for the PoC Trial as well as generating data for disease modelling work in the preclinical and prodromal phases of Alzheimer’s dementia. Objectives: The first data wave has been collected, quality checked, released and now available for analysis to answer numerous research questions. Here we describe the results from key variables in the EPAD LCS with the objective of using these results to compliment analyses of these data in the future. Design: EPAD LCS is a cohort study whose primary objective is as a readiness cohort for the EPAD PoC Trial. As such recruitment is not capped at any particular number but will continue to facilitate delivery of the EPAD PoC Trial. Research Participants are seen annually (with an additional 6 month visit in the first year). Setting: The EPAD Trial Delivery Network comprises currently 21 centres across Europe. Participants: Research participants are included if they are over 50 years old and do not have a diagnosis of dementia. Measurements: All research participants undergo multiple assessments to fully characterise the biology of Alzheimer’s disease and relate this to risk factors (both fixed and modifiable) and biomarker expression of disease through brain imaging, fluid samples (CSF, blood, urine and saliva), cognitive performance, functional abilities and neuropsychiatric symptomatology. Results: V500.0 represents the first 500 research participants baselined into EPAD LCS. The mean age was 66.4 (SD=6.7) and 47.8% were male. The data was split for presentation into 4 groups: [1] CDR=0 and Amyloid + (preclinical AD), [2] CDR=0 and Amyloid –, [3] CDR=0.5 and Amyloid + (prodromal AD) and [4] CDR=0.5 and Amyloid -. Conclusions: The EPAD LCS is achieving its primary objective of trial readiness and the structured approach to data release as manifest by this first data release of V500.0 will assist researchers to describe and compare their findings as well as in systematic reviews and meta-analyses. It is anticipated given current recruitment rates that V1500.0 data release will take place in Autumn 2019. V500.1 (when the 1 year follow up is completed on the V500.0 (sub)cohort will be in Autumn 2019 also.
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| 19. |
- Rosenberg, A., et al.
(författare)
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Multidomain Interventions to Prevent Cognitive Impairment, Alzheimer's Disease, and Dementia : From FINGER to World-Wide FINGERS
- 2020
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Ingår i: The Journal of Prevention of Alzheimer's Disease. - : SERDI. - 2274-5807 .- 2426-0266. ; 7:1, s. 29-36
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) and dementia are a global public health priority, and prevention has been highlighted as a pivotal component in managing the dementia epidemic. Modifiable risk factors of dementia and AD include lifestyle-related factors, vascular and metabolic disorders, and psychosocial factors. Randomized controlled clinical trials (RCTs) are needed to clarify whether modifying such factors can prevent or postpone cognitive impairment and dementia in older adults. Given the complex, multifactorial, and heterogeneous nature of late-onset AD and dementia, interventions targeting several risk factors and mechanisms simultaneously may be required for optimal preventive effects. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is the first large, long-term RCT to demonstrate that a multidomain lifestyle-based intervention ameliorating vascular and lifestyle-related risk factors can preserve cognitive functioning and reduce the risk of cognitive decline among older adults at increased risk of dementia. To investigate the multidomain intervention in other populations and diverse cultural and geographical settings, the World-Wide FINGERS (WW-FINGERS) network was recently launched (). Within this network, new FINGER-type trials with shared core methodology, but local culture and context-specific adaptations, will be conducted in several countries. The WW-FINGERS initiative facilitates international collaborations, provides a platform for testing multidomain strategies to prevent cognitive impairment and dementia, and aims at generating high-quality scientific evidence to support public health and clinical decision-making. Furthermore, the WW-FINGERS network can support the implementation of preventive strategies and translation of research findings into practice.
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| 20. |
- Saunders, T. S., et al.
(författare)
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Association between Longitudinal Cerebrospinal Fluid Alzheimer's Biomarkers and the Lifestyle for Brain Health (LIBRA) Index: Findings from the European Prevention of Alzheimer's Dementia Cohort Study (EPAD LCS)
- 2023
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Ingår i: Jpad-Journal of Prevention of Alzheimers Disease. - : SERDI. - 2274-5807 .- 2426-0266. ; 10:3, s. 543-550
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn the absence of preventative pharmacological interventions for Alzheimer's Disease dementia, there is a growing interest in modifiable risk factors associated with AD. Such risk factors are thought to contribute up to 40% of the risk of dementia. The Lifestyle for Brain Health (LIBRA) index, a dementia risk score which focuses exclusively on modifiable factors, has been found to be associated with increased risk of dementia and cognitive decline. It is currently unclear how the LIBRA index relates to cerebrospinal fluid (CSF) biomarkers of Alzheimer's Disease.ObjectivesTo examine the association between LIBRA index scores and trajectories of phospho-tau 181 and total tau in the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS), and to examine whether these trajectories differ between participants with high and low CSF amyloid-beta 1-42 (A beta 42).DesignAnalysis of CSF biomarker and LIBRA index scores from the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study.SettingThe European Prevention of Alzheimer's Dementia Longitudinal Cohort Study is a multi-centre, pan-European study.MeasurementsCerebrospinal fluid samples were taken by lumbar puncture and analysed using electrochemiluminescence. LIBRA index scores were calculated from self-reported variables, questionnaires, and physiological measurements.ResultIn the total sample (n = 1715; mean age = 66.0, 56.4% female), there were no significant associations between LIBRA scores (mean = 0.73 points) and rate of change in cerebrospinal fluid biomarkers. In participants with high A beta, reflecting less deposition in the brain, (n = 1134), LIBRA scores were significantly associated with the rate of change in total tau, where higher LIBRA scores (denoting higher dementia risk) were associated with increases in t-tau. There were no significant associations between LIBRA scores and change in cerebrospinal biomarkers in participants with low A beta.ConclusionWe found an association between modifiable risk factors and total tau accumulation in participants without dementia and without A beta accumulation. This suggests that increasing levels of total tau may be driven by factors other than A beta accumulation and highlights the need for developing and examining tau-targeting drugs in Alzheimer's Disease development.
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| 21. |
- Sindi, S., et al.
(författare)
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Multimodal Preventive Trial for Alzheimer’s Disease : MIND-ADmini Pilot Trial Study Design and Progress
- 2022
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Ingår i: The Journal of Prevention of Alzheimer's Disease. - : Serdi-Editions. - 2274-5807 .- 2426-0266. ; 9:1, s. 30-39
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Tidskriftsartikel (refereegranskat)abstract
- Background: Interventions simultaneously targeting multiple risk factors and mechanisms are most likely to be effective in preventing cognitive impairment. This was indicated in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) testing a multidomain lifestyle intervention among at-risk individuals. The importance of medical food at the early symptomatic disease stage, prodromal Alzheimer’s disease (AD), was emphasized in the LipiDiDiet trial. The feasibility and effects of multimodal interventions in prodromal AD are unclear. Objectives: To evaluate the feasibility of an adapted FINGER-based multimodal lifestyle intervention, with or without medical food, among individuals with prodromal AD. Methods: MIND-ADmini is a multinational proof-of-concept 6-month randomized controlled trial (RCT), with four trial sites (Sweden, Finland, Germany, France). The trial targeted individuals with prodromal AD defined using the International Working Group-1 criteria, and with vascular or lifestyle-related risk factors. The parallel-group RCT includes three arms: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management and social stimulation); 2) multimodal lifestyle intervention+medical food (Fortasyn Connect); and 3) regular health advice/ care (control group). Primary outcomes are feasibility and adherence. Secondary outcomes are adherence to the individual intervention domains and healthy lifestyle changes. Results: Screening began on 28 September 2017 and was completed on 21 May 2019. Altogether 93 participants were randomized and enrolled. The intervention proceeded as planned. Conclusions: For the first time, this pilot trial tests the feasibility and adherence to a multimodal lifestyle intervention, alone or combined with medical food, among individuals with prodromal AD. It can serve as a model for combination therapy trials (non-pharma, nutrition-based and/or pharmacological interventions).
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| 22. |
- Udeh-Momoh, C, et al.
(författare)
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Blood Derived Amyloid Biomarkers for Alzheimer's Disease Prevention
- 2022
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Ingår i: The journal of prevention of Alzheimer's disease. - : SERDI. - 2426-0266 .- 2274-5807. ; 9:1, s. 12-21
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Tidskriftsartikel (refereegranskat)abstract
- Background: Reliable, widely accessible and affordable biomarkers for predicting Alzheimer’s disease (AD) brain pathology status are a necessity to aid development of prevention strategies in cognitively healthy at-risk older adults, at the right timepoint. Measurements of the key neuropathological hallmark beta-amyloid (Aβ) by PET neuroimaging or cerebrospinal fluid measures reflect its accumulation in the brain, yet recent methodological advancements now enable blood-based measures reflecting cerebral amyloid burden. Objectives: The current study validated the capacity of plasma Aβ42/Aβ40 measured using six different assays to predict amyloid positivity in a subgroup of cognitively unimpaired (CU) participants in the ADNI study and assessed its ability to discriminate CU from AD cases. We also explored economic viability of using two different plasma amyloid assays for pre-screening in AD prevention trials and as routine clinical diagnostic tool, versus amyloid PET alone. Design: A cross-sectional analysis of plasma and brain amyloid data, including comparative cost analysis of the plasma biomarkers in relation to brain amyloid PET. Setting: Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants: ADNI participants consisting of 115 CU, mild cognitive impairment and AD cases who had plasma Aβ42/Aβ40 measured with six platforms. Measurements: Plasma Aβ42/Aβ40 was measured via six different platforms: three immunoassays (Roche, Quanterix and ADx Neurosciences) and three mass spectrometry (MS) based assays (WashU, Shimadzu and Gothenburg). Aβ-PET imaging was conducted within three months of plasma sampling using [18F]florbetapir. Results: There was a weak to moderate correlation of plasma Aβ42/Aβ40 ratio between platforms. The MS-based WashU test had the highest capacity to discriminate between CU and AD (area under the curve, AUC = 0.734, 95% CI: 0.613-0.854; P = 0.008). Within the CU group, the WashU plasma amyloid test had the best discriminative capacity to distinguish Aβ+ from Aβ– (AUC = 0.753, 95% CI: 0.601-0.905; P = 0.003) closely followed by the immunoassay from Roche (AUC = 0.737, 95% CI: 0.597-0.877; P = 0.006). The exploratory economic analyses showed that the use of Roche or WashU plasma amyloid assay as a pre-screening tool prior to Aβ-PET scans for clinical trial recruitment significantly reduced total screening cost (saving up to $5882 per recruited patient) expected in an AD prevention trial. Conclusions: With few available treatment strategies, dementia prevention is a global priority. CU individuals at risk for AD are the target population for dementia prevention but have been poorly studied. Our findings confirming diagnostic value of ultrasensitive immunoassays and high-performance immunoprecipitation coupled with MS for measurement of plasma Aβ42/Aβ40 to detect PET amyloid positivity in CU participants allude to potential clinical utility of this biomarker. Plasma Aβ42/Aβ40 could be optimal for pre-selecting at-risk candidates for more invasive and expensive investigations across AD prevention clinical trials and clinical care for a rapidly ageing population.
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| 23. |
- Yang, W., et al.
(författare)
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Association of Cognitive Reserve Indicator with Cognitive Decline and Structural Brain Differences in Middle and Older Age : Findings from the UK Biobank
- 2024
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Ingår i: The Journal of Prevention of Alzheimer's Disease. - 2274-5807 .- 2426-0266.
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundCognitive reserve (CR) contributes to preserving cognition when facing brain aging and damage. CR has been linked to dementia risk in late life. However, the association between CR and cognitive changes and brain imaging measures, especially in midlife, is unclear.ObjectiveWe aimed to explore the association of CR with cognitive decline and structural brain differences in middle and older age.DesignThis longitudinal study was from the UK Biobank project where participants completed baseline surveys between 2006 to 2010 and were followed (mean follow-up: 9 years). SettingA population-based study.ParticipantsA total of 42,301 dementia-free participants aged 40-70 were followed-up to detect cognitive changes. A subsample (n=34,041) underwent brain magnetic resonance imaging scans.MeasurementsWe used latent class analysis to generate a CR indicator (categorized as high, moderate, and low) based on education, occupation, and multiple cognitively stimulating activities. Cognitive tests for global and domain-specific cognition were administrated at baseline and follow-up. Total brain, white matter, grey matter, hippocampal, and white matter hyperintensity volumes (TBV, WMV, GMV, HV, and WMHV) were assessed at the follow-up examination. Data were analyzed using mixed-effects models and analysis of covariance.ResultsAt baseline, 16,032 (37.9%), 10,709 (25.3%), and 15,560 (36.8%) participants had low, moderate, and high levels of CR, respectively. Compared with low CR, high CR was associated with slower declines in global cognition (β [95% confidence interval]: 0.10 [0.08, 0.11]), prospective memory (0.10 [0.06, 0.15]), fluid intelligence (0.07 [0.04, 0.10]), and reaction time (0.04 [0.02, 0.06]). Participants with high CR had lower TBV, WMV, GMV, and WMHV, but higher HV when controlling for global cognition (corrected P <0.01 for all). The significant relationships between CR and cognition and TBV were present among both middle-aged (<60 years) and older (≥60 years) participants. The CR-cognition association remained significant despite reductions in brain structural properties.ConclusionsHigher CR is associated with slower cognitive decline, higher HV, and lower microvascular burden, especially in middle age. Individuals with high CR could tolerate smaller brain volumes while maintaining cognition. The benefit of CR for cognition is independent of structural brain differences. Our findings highlight the contribution of enhancing CR to helping compensate for neuroimaging alterations and ultimately prevent cognitive decline.
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| 24. |
- Önnestam, K., et al.
(författare)
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Safety, Tolerability, Pharmacokinetics and Quantitative Electroencephalography Assessment of ACD856, a Novel Positive Allosteric Modulator of Trk-Receptors Following Multiple Doses in Healthy Subjects
- 2023
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Ingår i: The Journal of Prevention of Alzheimer's Disease. - : Springer. - 2274-5807 .- 2426-0266. ; 10:4, s. 778-789
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundACD856 is a positive allosteric modulator of tropomyosin receptor kinase (Trk) receptors which has shown to have pro-cognitive and anti-depressant-like effects in various animal models. It is currently in clinical development for the treatment of Alzheimer’s disease and other disorders where cognition is impaired and is also considered for indications such as depression or other neuropsychiatric diseases. ACD856 has a novel mechanism of action modulating the activity of the Trk-receptors, resulting in increased stimulation of the neurotrophin signaling pathways. Previous studies applying single intravenous and oral doses of ACD856 indicate that ACD856 is safe and well-tolerated by healthy volunteer subjects, and that it has suitable safety and pharmacokinetic properties for further clinical development.ObjectivesTo investigate the safety and tolerability of 7 days of treatment with multiple ascending oral doses of ACD856 in healthy subjects, and to characterize its pharmacokinetic (PK) properties. In addition, pharmacodynamic effects of ACD856 using quantitative electroencephalography (qEEG) as an indicator for central target engagement were assessed.DesignThis was a prospective, phase I, double-blind, parallel-group, placebo-controlled, randomized study of the safety, tolerability, PK and pharmacodynamics of multiple ascending oral doses of ACD856 in healthy subjects. ACD856 or placebo were administered in 3 ascending dose cohorts of 8 subjects. Within each cohort, subjects were randomized to receive either ACD856 (n=6) or placebo (n=2).SettingThe study was conducted at a First-in-Human unit in Sweden.ParticipantsTwenty-four healthy male and female subjects.InterventionThe study medication was administered as an oral solution, with ACD856 or the same contents without the active ingredient (placebo). The dose levels ranged from 10 mg to 90 mg. ACD856 was administered once daily for 7 days, targeting steady state.MeasurementsSafety and tolerability assessments included adverse events, laboratory, vital signs, 12-lead electrocardiogram (ECG), physical examination, assessment of stool frequency and questionnaires to assess symptoms of anxiety, depression, as well as suicidal ideation and behavior. In addition, cardiodynamic ECGs were extracted to evaluate cardiac safety. PK parameters were calculated based on measured concentrations of ACD856 in plasma, urine, and cerebrospinal fluid (CSF) samples. Metabolite profiling, characterization and analysis was performed based on and urine samples. qEEG was recorded for patients in the two highest dose cohorts (30 and 90 mg/day) as a pharmacodynamic assessment to explore central target engagement.ResultsTreatment with ACD856 was well tolerated with no serious adverse events. No treatment emergent or dose related trends were observed for any of the safety assessments. ACD856 was rapidly absorbed and reached maximum plasma exposure at 30 to 45 minutes after administration. Steady state was reached before Day 6, with an elimination half-life at steady state of approximately 20 hours. At steady state, ACD856 exhibited accumulation ratios for Cmax and AUC of approximately 1.6 and 1.9 respectively. The exposure, Cmax and AUC0-24, increased proportionally with the dose. There was no unchanged ACD856 detected in urine. The metabolic pattern in urine and plasma was similar, and in alignment with the metabolites observed in preclinical toxicology studies. The level of ACD856 measured in CSF at steady state increased with dose, indicating Central Nervous System (CNS) exposure at relevant levels for pharmacodynamic effects. ACD856 demonstrated significant dose-dependent treatment-associated changes on qEEG parameters. Specifically, increase of the relative theta power and decrease of the fast alpha and beta power was observed, leading to an acceleration of the delta+theta centroid and an increase in the theta/beta ratio.ConclusionsACD856 was well tolerated at the tested dose levels (10–90 mg/daily for 7 days) in healthy subjects. The compound has a robust pharmacokinetic profile, with rapid absorption and dose-dependent exposure. ACD856 was shown to pass the blood-brain-barrier, reach relevant exposure in the CNS and to induce dose-dependent treatment-related changes on qEEG parameters, indicating central target engagement.
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| 25. |
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