Understanding multimorbidity requires sign-disease networks and higher-order interactions, a perspective.

Background: Count scores, disease clustering, and pairwise associations between diseases remain ubiquitous in multimorbidity research despite two major shortcomings: they yield no insight into plausible mechanisms underlying multimorbidity, and they ignore higher-order interactions such as effect modification. Objectives: We argue that two components are currently missing but vital to develop novel multimorbidity metrics. Firstly, networks should be constructed which consists simultaneously of signs, symptoms, and diseases, since only then could they yield insight into plausible shared biological mechanisms underlying diseases.Secondly, learning pairwise associations is insufficient to fully characterize the correlations in a system. That is, synergistic (e.g., cooperative or antagonistic) effects are widespread in complex systems, where two or more elements combined give a larger or smaller effect than the sum of their individual effects. It can even occur that pairs of symptoms have no pairwise associations whatsoever, but in combination have a significant association. Therefore, higher-order interactions should be included in networks used to study multimorbidity, resulting in so-called hypergraphs. Methods: We illustrate our argument using a synthetic Bayesian Network model of symptoms, signs and diseases, composed of pairwise and higher-order interactions. We simulate network interventions on both individual and population levels and compare the ground-truth outcomes with the predictions from pairwise associations. Conclusion: We find that, when judged purely from the pairwise associations, interventions can have unexpected 'side-effects' or the most opportune intervention could be missed. The hypergraph uncovers links missed in pairwise networks, giving a more complete overview of sign and disease associations.

Decision making under deep uncertainty for pandemic policy planning.

Policymakers around the world were generally unprepared for the global COVID-19 pandemic. As a result, the virus has led to millions of cases and hundreds of thousands of deaths. Theoretically, the number of cases and deaths did not have to happen (as demonstrated by the results in a few countries). In this pandemic, as in other great disasters, policymakers are confronted with what policy analysts call Decision Making under Deep Uncertainty (DMDU). Deep uncertainty requires policies that are not based on 'predict and act' but on 'prepare, monitor, and adapt', enabling policy adaptations over time as events occur and knowledge is gained. We discuss the potential of a DMDU-approach for pandemic decisionmaking.

The Impact of Payment Reforms on the Quality and Utilisation of Healthcare for Patients With Multimorbidity: A Systematic Review.

Inadequate treatment of multimorbidity is recognised as a major determinant of the effectiveness of healthcare and also of its inappropriate expenditures. However, current payment systems target, primarily, the treatment of single diseases, thus hindering integrated delivery of care for patients with multimorbidity (PwM). This review aims to assess the effects of targeted reforms of payment systems which could help attain a higher quality of care and reduce unnecessary healthcare utilisation. In June 2020, a search of Medline and EMBASE revealed 13 relevant articles. The most common payment models were the use of bundled payments (n = 4) and diagnosis-related group payments (n = 4). Except for an increase in hospital admissions (n = 3), no outcome showed unambiguous significant effects across more than one study. The two studies which focused explicitly on PwM showed a significant decrease in 30-day hospital readmissions. This, however, was not maintained after 60 days in one study. No general conclusion could be drawn on the effects of targeted payment reforms for PwM. Our findings suggest that reforms should be combined with more multifaceted healthcare delivery to address the complex patterns of healthcare use effectively. Thorough evaluations of targeted payment reforms are needed urgently to contribute to the body of evidence required.

Characteristics of subjective cognitive decline associated with amyloid positivity.

INTRODUCTION: The evidence for characteristics of persons with subjective cognitive decline (SCD) associated with amyloid positivity is limited. METHODS: In 1640 persons with SCD from 20 Amyloid Biomarker Study cohort, we investigated the associations of SCD-specific characteristics (informant confirmation, domain-specific complaints, concerns, feelings of worse performance) demographics, setting, apolipoprotein E gene (APOE) ε4 carriership, and neuropsychiatric symptoms with amyloid positivity. RESULTS: Between cohorts, amyloid positivity in 70-year-olds varied from 10% to 76%. Only older age, clinical setting, and APOE ε4 carriership showed univariate associations with increased amyloid positivity. After adjusting for these, lower education was also associated with increased amyloid positivity. Only within a research setting, informant-confirmed complaints, memory complaints, attention/concentration complaints, and no depressive symptoms were associated with increased amyloid positivity. Feelings of worse performance were associated with less amyloid positivity at younger ages and more at older ages. DISCUSSION: Next to age, setting, and APOE ε4 carriership, SCD-specific characteristics may facilitate the identification of amyloid-positive individuals.

The conundrum of human immune system "senescence".

There is a great deal of debate on the question of whether or not we know what ageing is (Ref. Cohen et al., 2020). Here, we consider what we believe to be the especially confused and confusing case of the ageing of the human immune system, commonly referred to as "immunosenescence". But what exactly is meant by this term? It has been used loosely in the literature, resulting in a certain degree of confusion as to its definition and implications. Here, we argue that only those differences in immune parameters between younger and older adults that are associated in some definitive manner with detrimental health outcomes and/or impaired survival prospects should be classed as indicators of immunosenescence in the strictest sense of the word, and that in humans we know remarkably little about their identity. Such biomarkers of immunosenescence may nonetheless indicate beneficial effects in other contexts, consistent with the notion of antagonistic pleiotropy. Identifying what could be true immunosenescence in this respect requires examining: (1) what appears to correlate with age, though generality across human populations is not yet confirmed; (2) what clearly is part of a suite of canonical changes in the immune system that happen with age; (3) which subset of those changes accelerates rather than slows aging; and (4) all changes, potentially population-specific, that accelerate agig. This remains an immense challenge. These questions acquire an added urgency in the current SARS-CoV-2 pandemic, given the clearly greater susceptibility of older adults to COVID-19.

Geriatric Education Programs for Emergency Department Professionals: A Systematic Review.

OBJECTIVES: To evaluate geriatric education programs for emergency department (ED) professionals based on: content and teaching methods and learning outcome effects and factors promoting or hindering program implementation. DESIGN: Systematic review. SETTING: ED. PARTICIPANTS: Physicians, nurses, and medical residents working in the ED. METHODS AND MEASUREMENT: Five major biomedical databases were searched for (quasi) experimental studies, published between 1990 and April 2018, evaluating geriatric education programs for ED professionals. Data were synthesized around study quality, learning participants, teaching content and methods, and Kirkpatrick learning outcomes. RESULTS: Nine before-after studies were included. Learners were mostly ED residents and, to a smaller extent, ED nurses and physicians. Study quality was moderate, with the lowest scores on sampling and instrument validity. Programs varied from a 1-day workshop to a 2-year curriculum, mostly combining didactic lectures with active and experiential learning formats. Topics commonly addressed included managing: geriatric syndromes, trauma and falls, medication, atypical presentations, and care transitions. Statistically significant improvements were mostly found in learners' knowledge acquisition (six studies). Significant improvements were also found in single studies on: self-reported geriatric screening, documentation of geriatric care, and appropriate urinary catheter placement. Factors promoting program implementation included: solving competing educational demands and busy work schedules, embedding the program in preexisting curricula, and close collaboration between emergency and geriatric medicine faculties. CONCLUSIONS: Various geriatric education programs improve the geriatric knowledge of ED professionals and seem to positively impact their clinical practice. However, more program evaluations with larger study samples, and use of valid and reliable outcome measures, are needed to provide robust evidence on the effectiveness of such programs. J Am Geriatr Soc, 1-8, 2019. J Am Geriatr Soc 67:2402-2409, 2019.

Delirium After Transcatheter Aortic Valve Implantation Under General Anesthesia: Incidence, Predictors, and Relation to Long-Term Survival.

BACKGROUND/OBJECTIVES: Prospectively collected data on postoperative delirium (POD) after transcatheter aortic valve implantation (TAVI) are scarce. The aim of this study was to report the incidence and risk factors of delirium after TAVI under general anesthesia and to assess the association of POD with clinical outcome and short- and long-term survival. DESIGN: Prospective cohort study. SETTING: Academic medical center. PARTICIPANTS: A total of 703 subsequent patients undergoing TAVI under general anesthesia between 2008 and 2017. MEASUREMENTS: Delirium was assessed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), criteria. Outcomes were postprocedural clinical outcome and short- and long-term survival (30 days and 5 years, respectively). RESULTS: POD was observed in 16.5% (116/703), was the strongest independent predictor of long-term mortality (hazard ratio = 1.91; 95% confidence interval [CI] = 1.36-2.70), and was associated with impaired 30-day and 5-year survival (92.2% vs 96.8% [P = .025] and 40.0% vs 50.0% [P = .007], respectively). Stroke and new onset of atrial fibrillation were more often observed in delirious patients (6.9% vs 1.9% and 12.1% vs 5.1%, respectively). Strongest independent predictors of POD were prior delirium (odds ratio [OR] = 2.56; 95% CI = 1.52-4.31) and aortic valve area less than 0.75 cm2 (OR = 2.39; 95% CI = 1.53-3.74). CONCLUSION: One in six patients experienced POD after TAVI under general anesthesia. POD was the strongest predictor of long-term mortality and was associated with impaired short- and long-term survival. Prior delirium and a more calcified aortic valve were the strongest independent predictors of POD. J Am Geriatr Soc 67:2325-2330, 2019.

Is every-day walking in older adults more analogous to dual-task walking or to usual walking? Elucidating the gaps between gait performance in the lab and during 24/7 monitoring.

BACKGROUND: The traditional evaluation of gait in the laboratory during structured testing has provided important insights, but is limited by its "snapshot" character and observation in an unnatural environment. Wearables enable monitoring of gait in real-world environments over a week. Initial findings show that in-lab and real-world measures differ. As a step towards better understanding these gaps, we directly compared in-lab usual-walking (UW) and dual-task walking (DTW) to daily-living measures of gait. METHODS: In-lab gait features (e.g., gait speed, step regularity, and stride regularity) derived from UW and DTW were compared to the same gait features during daily-living in 150 elderly fallers (age: 76.5 ± 6.3 years, 37.6% men). In both settings, features were extracted from a lower-back accelerometer. In the real-world setting, subjects were asked to wear the device for 1 week and pre-processing detected 30-s daily-living walking bouts. A histogram of all walking bouts was determined for each walking feature for each subject and then each subject's typical (percentile 50, median), worst (percentile 10) and the best (percentile 90) values over the week were determined for each feature. Statistics of reliability were assessed using Intra-Class correlations and Bland-Altman plots. RESULTS: As expected, in-lab gait speed, step regularity, and stride regularity were worse during DTW, compared to UW. In-lab gait speed, step regularity, and stride regularity during UW were significantly higher (i.e., better) than the typical daily-living values (p < 0.001) and different (p < 0.001) from the worst and best values. DTW values tended to be similar to typical daily-living values (p = 0.205, p = 0.053, p = 0.013 respectively). ICC assessment and Bland-Altman plots indicated that in-lab values do not reliably reflect the daily-walking values. CONCLUSIONS: Gait values measured during relatively long (30-s) daily-living walking bouts are more similar to the corresponding values obtained in the lab during dual-task walking, as compared to usual walking. Still, gait performance during most daily-living walking bouts is worse than that measured during usual and dual-tasking in the lab. The values measured in the lab do not reliably reflect daily-living measures. That is, an older adult's typical daily-living gait cannot be estimated by simply measuring walking in a structured, laboratory setting.

Correction to: Cerebrovascular and amyloid pathology in predementia stages: the relationship with neurodegeneration and cognitive decline.

Upon publication of this article [1], it was noticed that there were some inconsistencies in Tables 1, 2 and 3. Some of the superscript letters were incorrectly assigned. Please see below the correct tables.

Association Between Later Life Lifestyle Factors and Alzheimer's Disease Biomarkers in Non-Demented Individuals: A Longitudinal Descriptive Cohort Study.

BACKGROUND: Lifestyle factors have been associated with the risk of dementia, but the association with Alzheimer's disease (AD) remains unclear. OBJECTIVE: To examine the association between later life lifestyle factors and AD biomarkers (i.e., amyloid-ß 1-42 (Aß42) and tau in cerebrospinal fluid (CSF), and hippocampal volume) in individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). In addition, to examine the effect of later life lifestyle factors on developing AD-type dementia in individuals with MCI. METHODS: We selected individuals with SCD (n = 111) and MCI (n = 353) from the DESCRIPA and Kuopio Longitudinal MCI studies. CSF Aß42 and tau concentrations were assessed with ELISA assay and hippocampal volume with multi-atlas segmentation. Lifestyle was assessed by clinical interview at baseline for: social activity, physical activity, cognitive activity, smoking, alcohol consumption, and sleep. We performed logistic and Cox regression analyses adjusted for study site, age, gender, education, and diagnosis. Prediction for AD-type dementia was performed in individuals with MCI only. RESULTS: Later life lifestyle factors were not associated with AD biomarkers or with conversion to AD-type dementia. AD biomarkers were strongly associated with conversion to AD-type dementia, but these relations were not modulated by lifestyle factors. Apolipoprotein E (APOE) genotype did not influence the results. CONCLUSIONS: Later life lifestyle factors had no impact on key AD biomarkers in individuals with SCD and MCI or on conversion to AD-type dementia in MCI.

Clinical Relevance of Differences in Glomerular Filtration Rate Estimations in Frail Older People by Creatinine- vs. Cystatin C-Based Formulae.

BACKGROUND: The risk of incorrect medication dosing is high in frail older people. Therefore, accurate assessment of the glomerular filtration rate is important. OBJECTIVE: The objective of this study was to compare the estimated glomerular filtration rate using creatinine- and cystatin C-based formulae, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, in frail older people. We hypothesized that frailty determines the difference between the creatinine- and cystatin C-based formulae. METHODS: The mean difference between CKD-EPI creatinine and cystatin C was determined using (cross-sectional) data of 55 patients (mean age 73 years) admitted to a psychiatric ward for older adults. The level of agreement of these estimations was assessed by a Bland-Altman analysis. In all patients, the Rockwood's Frailty Index was derived and correlated with the mean difference between CKD-EPI creatinine and cystatin C. RESULTS: The mean difference between CKD-EPI creatinine (mean 71.2 mL/min/1.73 m2) and CKD-EPI cystatin C (mean 57.6 mL/min/1.73 m2) was 13.6 mL/min/1.73 m2 (p < 0.0001). The two standard deviation limit in the Bland-Altman plot was large (43.2 mL/min/1.73 m2), which represents a low level of agreement. The Frailty Index did not correlate with the mean difference between the creatinine- and cystatin C-based glomerular filtration rate (Pearson correlation coefficient 0.182, p = 0.184). CONCLUSIONS: There was a significant gap between a creatinine- and cystatin C-based estimation of glomerular filtration rate, irrespective of frailty. The range of differences between the commonly used estimated glomerular filtration rate formulae might result in clinically relevant differences in drug prescription and differences in chronic kidney disease staging.

White Matter Hyperintensities Potentiate Hippocampal Volume Reduction in Non-Demented Older Individuals with Abnormal Amyloid-ß.

Cerebral small vessel disease (cSVD) and amyloid-ß (Aß) deposition often co-exist in (prodromal) dementia, and both types of pathology have been associated with neurodegeneration. We examined whether cSVD and Aß have independent or interactive effects on hippocampal volume (HV) in a memory clinic population. We included 87 individuals with clinical diagnoses of Alzheimer's disease (AD) (n = 24), mild cognitive impairment (MCI) (n = 26), and subjective cognitive complaints (SCC) (n = 37). cSVD magnetic resonance imaging markers included white matter hyperintensity (WMH) volume, lacunar infarct presence, and microbleed presence. Aß pathology was assessed as cerebrospinal fluid-derived Aß1 - 42 levels and dichotomized into normal or abnormal, and HV was determined by manual volumetric measurements. A linear hierarchical regression approach was applied for the detection of additive or interaction effects between cSVD and Aß on HV in the total participant group (n = 87) and in the non-demented group (including SCC and MCI individuals only, n = 63). The results revealed that abnormal Aß and lacunar infarct presence were independently associated with lower HV in the non-demented individuals. Interestingly, Aß and WMH pathology interacted in the non-demented individuals, such that WMH had a negative effect on HV in individuals with abnormal CSF Aß42 levels, but not in individuals with normal CSF Aß42 levels. These associations were not present when individuals with AD were included in the analyses. Our observations suggest that relatively early on in the disease process older individuals with abnormal Aß levels are at an increased risk of accelerated disease progression when concomitant cSVD is present.

The Diagnostic and Prognostic Value of Neuropsychological Assessment in Memory Clinic Patients.

BACKGROUND: Neuropsychological testing has long been embedded in daily clinical practice at memory clinics but the added value of a complete neuropsychological assessment (NPA) to standard clinical evaluation is unknown. OBJECTIVE: To evaluate the added diagnostic and prognostic value of NPA to clinical evaluation only in memory clinic patients. METHODS: In 221 memory clinic patients of a prospective cohort study, clinical experts diagnosed clinical syndrome (subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or dementia) and etiology (Alzheimer's disease (AD) or no AD), and provided a prognosis of disease course (decline or no decline) before and after results of NPA were made available. The reference standard was a panel consensus based on all clinical information at baseline and up to 2 follow-up assessments. RESULTS: With NPA data available, clinicians changed their initial syndromal diagnosis in 22% of patients, and the etiological diagnosis as well as the prognosis in 15%. This led to an increase in correctly classified cases of 18% for syndromal diagnosis, 5% for etiological diagnosis, and 1% for prognosis. NPA data resulted in the largest improvement in patients initially classified as SCI (syndrome: 93.3% (n = 14) correctly reclassified, etiology: net reclassification improvement [NRI] = 0.61, prognosis: NRI = 0.13) or MCI (syndrome: 89.3% (n = 23) correctly reclassified, etiology: NRI = 0.17, prognosis: NRI = 0.14), while there was no improvement in patients with dementia (syndrome: 100% (n = 1) correctly reclassified, etiology: NRI = -0.05, prognosis: NRI = -0.06). Overall, inclusion of NPA in the diagnostic process increased confidence in all diagnoses with 6-7%. CONCLUSION: Administration of a complete NPA after standard clinical evaluation has added value for diagnosing cognitive syndrome and its underlying etiology in patients regarded as non-demented based on the first clinical impression.

Addition of a non-immersive virtual reality component to treadmill training to reduce fall risk in older adults (V-TIME): a randomised controlled trial.

BACKGROUND: Age-associated motor and cognitive deficits increase the risk of falls, a major cause of morbidity and mortality. Because of the significant ramifications of falls, many interventions have been proposed, but few have aimed to prevent falls via an integrated approach targeting both motor and cognitive function. We aimed to test the hypothesis that an intervention combining treadmill training with non-immersive virtual reality (VR) to target both cognitive aspects of safe ambulation and mobility would lead to fewer falls than would treadmill training alone. METHODS: We carried out this randomised controlled trial at five clinical centres across five countries (Belgium, Israel, Italy, the Netherlands, and the UK). Adults aged 60-90 years with a high risk of falls based on a history of two or more falls in the 6 months before the study and with varied motor and cognitive deficits were randomly assigned by use of computer-based allocation to receive 6 weeks of either treadmill training plus VR or treadmill training alone. Randomisation was stratified by subgroups of patients (those with a history of idiopathic falls, those with mild cognitive impairment, and those with Parkinson's disease) and sex, with stratification per clinical site. Group allocation was done by a third party not involved in onsite study procedures. Both groups aimed to train three times per week for 6 weeks, with each session lasting about 45 min and structured training progression individualised to the participant's level of performance. The VR system consisted of a motion-capture camera and a computer-generated simulation projected on to a large screen, which was specifically designed to reduce fall risk in older adults by including real-life challenges such as obstacles, multiple pathways, and distracters that required continual adjustment of steps. The primary outcome was the incident rate of falls during the 6 months after the end of training, which was assessed in a modified intention-to-treat population. Safety was assessed in all patients who were assigned a treatment. This study is registered with ClinicalTrials.gov, NCT01732653. FINDINGS: Between Jan 6, 2013, and April 3, 2015, 302 adults were randomly assigned to either the treadmill training plus VR group (n=154) or treadmill training alone group (n=148). Data from 282 (93%) participants were included in the prespecified, modified intention-to-treat analysis. Before training, the incident rate of falls was similar in both groups (10·7 [SD 35·6] falls per 6 months for treadmill training alone vs 11·9 [39·5] falls per 6 months for treadmill training plus VR). In the 6 months after training, the incident rate was significantly lower in the treadmill training plus VR group than it had been before training (6·00 [95% CI 4·36-8·25] falls per 6 months; p<0·0001 vs before training), whereas the incident rate did not decrease significantly in the treadmill training alone group (8·27 [5·55-12·31] falls per 6 months; p=0·49). 6 months after the end of training, the incident rate of falls was also significantly lower in the treadmill training plus VR group than in the treadmill training group (incident rate ratio 0·58, 95% CI 0·36-0·96; p=0·033). No serious training-related adverse events occurred. INTERPRETATION: In a diverse group of older adults at high risk for falls, treadmill training plus VR led to reduced fall rates compared with treadmill training alone. FUNDING: European Commission.

Added Prognostic Value of Cerebrospinal Fluid Biomarkers in Predicting Decline in Memory Clinic Patients in a Prospective Cohort.

BACKGROUND: Limited information is available on short-term prognosis of Alzheimer's disease (AD) biomarkers in cerebrospinal fluid (CSF) in addition to routine diagnostic workup. OBJECTIVE: This study aims to investigate the added prognostic value of AD CSF biomarkers. METHODS: In a prospective cohort study, clinical experts predicted cognitive and functional symptoms in 114 memory clinic patients by assessing comprehensive routine diagnostic test information (patient history, and physical, neurological, psychiatric, neuropsychological, and MRI examinations), without and with CSF biomarkers. The reference standard was the 'observed clinically relevant decline' using baseline and 1- and 2-year follow-up information. RESULTS: Decline over a 2-year period was observed in 51% of all participants (3% in SMC, 48% in MCI, 90% in mild dementia). In the total sample, the accuracy of predicted decline did not differ significantly between routine assessment without (79% correctly predicted) and with (74% correctly predicted) CSF biomarkers. Subgroup analyses revealed 25 (83%) correct predictions in SMC, 30 (68%) in MCI, and 35 (88%) in dementia without the use of CSF; and 21 (70%), 27 (61%), and 36 (90%), respectively, with the use of CSF in addition to the routine assessment. CONCLUSION: AD CSF biomarkers did not increase accuracy of 2-year prognosis of cognitive and functional decline when added to routine diagnostic workup. This suggests that the standard diagnostic workup without CSF biomarkers allows fairly accurate predictions for the short-term course of symptoms. Routine AD biomarkers in CSF have limited prognostic value over 2 years in persons with a suspected cognitive disorder.

DNMT3A moderates cognitive decline in subjects with mild cognitive impairment: replicated evidence from two mild cognitive impairment cohorts.

Epigenetic dysregulation has been associated with cognitive decline and Alzheimer's disease. The present study investigated associations between common SNPs in genes regulating DNA methylation and age-related changes in cognitive decline in two independent prospective cohorts of patients suffering from mild cognitive impairment. An association between the rs1187120 SNP in DNMT3A and annual decline in cognitive functioning was discovered and replicated, suggesting that DNMT3A moderates cognitive decline in subjects with mild cognitive impairment.

The use of biomarkers for the etiologic diagnosis of MCI in Europe: an EADC survey.

We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aß42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.

Development of an international schedule for the assessment and staging of care for dementia.

BACKGROUND: A reliable and valid global staging scale has been lacking within dementia care. OBJECTIVE: To develop an easy-to-use multi-dimensional clinical staging schedule for dementia. METHODS: The schedule was developed through: i) Two series of focus groups (40 and 48 participants, respectively) in Denmark, France, Germany, Netherlands, Spain, Switzerland, and UK with a multi-disciplinary group of professionals working within dementia care, to assess the need for a dementia-staging tool and to obtain suggestions on its design and characteristics; ii) A pilot-study over three rounds to test inter-rater reliability of the newly developed schedule using written case histories, with five members of the project's steering committee and 27 of their colleagues from Netherlands, France, and Spain as participants; and iii) A field-study to test the schedule's inter-rater reliability in clinical practice in France, Germany, Netherlands, Spain, Italy, Turkey, South Korea, Romania, and Serbia, which included 209 dementia patients and 217 of their caregivers as participants. RESULTS: Focus group participants indicated a clear need for a culture-fair international dementia staging scale and reached consensus on face validity and content validity. Accordingly, the schedule has been composed of seven dimensions including behavioral, cognitive, physical, functional, social, and care aspects. Overall, the schedule showed adequate face validity, content validity, and inter-rater reliability; in the nine field-sites, intraclass correlation coefficients (ICCs; absolute agreement) for individual dimensions ranged between 0.38 and 1.0, with 84.4% of ICCs over 0.7. ICCs for total sum scores ranged between 0.89 and 0.99 in the nine field-sites. CONCLUSION: The IDEAL schedule looks promising as tool for the clinical and social management of people with dementia globally, though further reliability and validity testing is needed.