The 2022 symposium on dementia and brain aging in low- and middle-income countries: Highlights on research, diagnosis, care, and impact.

Two of every three persons living with dementia reside in low- and middle-income countries (LMICs). The projected increase in global dementia rates is expected to affect LMICs disproportionately. However, the majority of global dementia care costs occur in high-income countries (HICs), with dementia research predominantly focusing on HICs. This imbalance necessitates LMIC-focused research to ensure that characterization of dementia accurately reflects the involvement and specificities of diverse populations. Development of effective preventive, diagnostic, and therapeutic approaches for dementia in LMICs requires targeted, personalized, and harmonized efforts. Our article represents timely discussions at the 2022 Symposium on Dementia and Brain Aging in LMICs that identified the foremost opportunities to advance dementia research, differential diagnosis, use of neuropsychometric tools, awareness, and treatment options. We highlight key topics discussed at the meeting and provide future recommendations to foster a more equitable landscape for dementia prevention, diagnosis, care, policy, and management in LMICs. HIGHLIGHTS: Two-thirds of persons with dementia live in LMICs, yet research and costs are skewed toward HICs. LMICs expect dementia prevalence to more than double, accompanied by socioeconomic disparities. The 2022 Symposium on Dementia in LMICs addressed advances in research, diagnosis, prevention, and policy. The Nairobi Declaration urges global action to enhance dementia outcomes in LMICs.

Structural equation modeling for identifying the drivers of health-related quality of life improvement experienced by patients with migraine receiving eptinezumab.

BACKGROUND: As new migraine therapies emerge, it is crucial for measures to capture the complexities of health-related quality of life (HRQoL) improvement beyond improvements in monthly migraine day (MMD) reduction. Investigations into the correlations between MMD reduction, symptom management, and HRQoL are lacking, particularly those that focus on improvements in canonical symptoms and improvement in patient-identified most-bothersome symptoms (PI-MBS), in patients treated with eptinezumab. This exploratory analysis identified efficacy measures mediating the effect of eptinezumab on HRQoL improvements in patients with migraine. METHODS: Data from the DELIVER study of patients with 2-4 prior preventive migraine treatment failures (NCT04418765) were inputted to two structural equation models describing sources of HRQoL improvement via Migraine-Specific Quality-of-Life Questionnaire (MSQ) scores. A single latent variable was defined to represent HRQoL and describe the sources of HRQoL in DELIVER. One model included all migraine symptoms while the second model included the PI-MBS as the only migraine symptom. Mediating variables capturing different aspects of efficacy included MMDs, other canonical symptoms, and PI-MBS. RESULTS: In the first model, reductions in MMDs and other canonical symptoms accounted for 35% (standardized effect size [SES] - 0.11) and 25% (SES - 0.08) of HRQoL improvement, respectively, with 41% (SES - 0.13) of improvement comprising "direct treatment effect," i.e., unexplained by mediators. In the second model, substantial HRQoL improvement with eptinezumab (86%; SES - 0.26) is due to MMD reduction (17%; SES - 0.05) and change in PI-MBS (69%; SES - 0.21). CONCLUSIONS: Improvements in HRQoL experienced by patients treated with eptinezumab can be substantially explained by its effect on migraine frequency and PI-MBS. Therefore, in addition to MMD reduction, healthcare providers should discuss PI-MBS improvements, since this may impact HRQoL. Health technology policymakers should consider implications of these findings in economic evaluation, as they point to alternative measurement of quality-adjusted life years to capture fully treatment benefits in cost-utility analyses. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT04418765 ; EudraCT (Identifier: 2019-004497-25; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004497-25 ).

Progression analysis versus traditional methods to quantify slowing of disease progression in Alzheimer's disease.

BACKGROUND: The clinical meaningfulness of the effects of recently approved disease-modifying treatments (DMT) in Alzheimer's disease is under debate. Available evidence is limited to short-term effects on clinical rating scales which may be difficult to interpret and have limited intrinsic meaning to patients. The main value of DMTs accrues over the long term as they are expected to cause a delay or slowing of disease progression. While awaiting such evidence, the translation of short-term effects to time delays or slowing of progression could offer a powerful and readily interpretable representation of clinical outcomes. METHODS: We simulated disease progression trajectories representing two arms, active and placebo, of a hypothetical clinical trial of a DMT. The placebo arm was simulated based on estimated mean trajectories of clinical dementia rating scale-sum of boxes (CDR-SB) recordings from amyloid-positive subjects with mild cognitive impairment (MCI) from Alzheimer's Disease Neuroimaging Initiative (ADNI). The active arm was simulated to show an average slowing of disease progression versus placebo of 20% at each visit. The treatment effects in the simulated trials were estimated with a progression model for repeated measures (PMRM) and a mixed model for repeated measures (MMRM) for comparison. For PMRM, the treatment effect is expressed in units of time (e.g., days) and for MMRM in units of the outcome (e.g., CDR-SB points). PMRM results were implemented in a health economics Markov model extrapolating disease progression and death over 15 years. RESULTS: The PMRM model estimated a 19% delay in disease progression at 18 months and 20% (~ 7 months delay) at 36 months, while the MMRM model estimated a 25% reduction in CDR-SB (~ 0.5 points) at 36 months. The PMRM model had slightly greater power compared to MMRM. The health economic model based on the estimated time delay suggested an increase in life expectancy (10 months) without extending time in severe stages of disease. CONCLUSION: PMRM methods can be used to estimate treatment effects in terms of slowing of progression which translates to time metrics that can be readily interpreted and appreciated as meaningful outcomes for patients, care partners, and health care practitioners.

Associations of Orthostatic Hypotension and Frailty With Dementia and Mortality in Older Adults: A Population-Based Cohort Study.

BACKGROUND: This study aimed to assess the associations of orthostatic hypotension (OH), in the presence or absence of frailty, with dementia and mortality in older adults. METHODS: We conducted a 15-year population-based cohort study including 2 703 baseline dementia-free individuals from the Swedish National Study on Aging and Care in Kungsholmen. At baseline, OH was defined as a decline in systolic/diastolic blood pressure ≥20/10 mm Hg 1 minute after standing up from a supine position. Frailty status was defined following Fried's frailty phenotype. Dementia was diagnosed following the Diagnostic and Statistical Manual of Mental Disorders-fourth edition criteria. Multistate flexible parametric survival models were used to estimate associations of OH and frailty with dementia and mortality. RESULTS: Robust people with OH (adjusted hazard ratio [HR] = 2.28; 95% confidence interval [CI] = 1.47-3.54) and frail people without OH (HR = 1.98; 95% CI = 1.40-2.82) or with OH (HR = 2.73; 95% CI = 1.82-4.10) had a higher dementia risk than OH-free and robust people. Moreover, frail people, independently of the presence of OH, had higher mortality rate than OH-free and robust people. In individuals who developed dementia during the follow-up period, neither OH nor frailty was significantly associated with mortality. CONCLUSIONS: Older adults with OH, whether robust or frail, may have a higher dementia risk than those without OH. Older adults with OH, when having frailty, may have a higher mortality rate than those without OH. The concurrent assessments of OH and frailty may provide prognostic values in terms of dementia and mortality risk in older adults.

Predicting sojourn times across dementia disease stages, institutionalization, and mortality.

INTRODUCTION: Inferring the timeline from mild cognitive impairment (MCI) to severe dementia is pivotal for patients, clinicians, and researchers. Literature is sparse and often contains few patients. We aim to determine the time spent in MCI, mild-, moderate-, severe dementia, and institutionalization until death. METHODS: Multistate modeling with Cox regression was used to obtain the sojourn time. Covariates were age at baseline, sex, amyloid status, and Alzheimer's disease (AD) or other dementia diagnosis. The sample included a register (SveDem) and memory clinics (Amsterdam Dementia Cohort and Memento). RESULTS: Using 80,543 patients, the sojourn time from clinically identified MCI to death across all patient groups ranged from 6.20 (95% confidence interval [CI]: 5.57-6.98) to 10.08 (8.94-12.18) years. DISCUSSION: Generally, sojourn time was inversely associated with older age at baseline, males, and AD diagnosis. The results provide key estimates for researchers and clinicians to estimate prognosis.

People get ready! A new generation of Alzheimer's therapies may require new ways to deliver and pay for healthcare.

The development of disease-modifying therapies (DMTs) for Alzheimer's disease (AD) has progressed over the last decade, and the first-ever therapies with potential to slow the progression of disease are approved in the United States. AD DMTs could provide life-changing opportunities for people living with this disease, as well as for their caregivers. They could also ease some of the immense societal and economic burden of dementia. However, AD DMTs also come with major challenges due to the large unmet medical need, high prevalence of AD, new costs related to diagnosis, treatment and monitoring, and uncertainty in the therapies' actual clinical value. This perspective article discusses, from the broad perspective of various health systems and stakeholders, how we can overcome these challenges and improve society's readiness for AD DMTs. We propose that innovative payment models such as performance-based payments, in combination with learning healthcare systems, could be the way forward to enable timely patient access to treatments, improve accuracy of cost-effectiveness evaluations and overcome budgetary barriers. Other important considerations include the need for identification of key drivers of patient value, the relevance of different economic perspectives (i.e. healthcare vs. societal) and ethical questions in terms of treatment eligibility criteria.

Health-related quality of life in subjective cognitive decline and mild cognitive impairment: a longitudinal cohort analysis.

BACKGROUND: Health-related quality of life (HR-QoL) is an important outcome for patients and crucial for demonstrating the value of new treatments. Health utility estimates in subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are limited, especially in biomarker-confirmed populations. Besides, little is known about the longitudinal HR-QoL trajectory. This study aims to provide health utility estimates for SCD and MCI and investigate the QoL trajectory along the disease continuum. METHODS: Longitudinal data from 919 SCD and 1336 MCI patients from the MEMENTO cohort were included. SCD was defined as clinical dementia rating (CDR) = 0, and MCI as CDR = 0.5. HR-QoL was measured using the EQ-5D-3L patient-reported instrument. Linear mixed-effect models (LMM) were used to assess the longitudinal change in HR-QoL and identify predictors of these changes. RESULTS: Baseline health utilities were 0.84 ± 0.16 and 0.81 ± 0.18, and visual analogue scale (VAS) were 75.8 ± 14.82 and 70.26 ± 15.77 in SCD and MCI. In amyloid-confirmed cases, health utilities were 0.85 ± 0.14 and 0.86 ± 0.12 in amyloid-negative and amyloid-positive SCD, and 0.83 ± 0.17 and 0.84 ± 0.16 in amyloid-negative and amyloid-positive MCI. LMM revealed an annual decline in health utility of - 0.015 (SE = 0.006) and - 0.09 (SE = 0.04) in moderate and severe dementia (P < 0.05). There was a negative association between clinical stage and VAS where individuals with MCI, mild, moderate, and severe dementia were on average 1.695 (SE = 0.274), 4.401 (SE = 0.676), 4.999 (SE = 0.8), and 15.386 (SE = 3.142) VAS points lower than individuals with SCD (P < 0.001). Older age, female sex, higher body mass index, diabetes, cardiovascular history, depression, and functional impairment were associated with poor HR-QoL. Amyloid positivity was associated with an annual decline of - 0.011 (SE = 0.004, P < 0.05) health utility over time. CONCLUSIONS: Health utility estimates from this study can be used in economic evaluations of interventions targeting SCD and MCI. Health utility declines over time in moderate and severe dementia, and VAS declines with advancing clinical stages. Amyloid-positive patients show a faster decline in health utility indicating the importance of considering biomarker status in HR-QoL assessments. Future research is needed to confirm the longitudinal relationship between amyloid status and HR-QoL and to examine the level at which depression and IADL contribute to HR-QoL decline in AD.

Precision medicine in neurodegeneration: the IHI-PROMINENT project.

Neurodegenerative diseases are one of the most important contributors to morbidity and mortality in the elderly. In Europe, over 14 million people are currently living with dementia, at a cost of over 400 billion EUR annually. Recent advances in diagnostics and approval for new pharmaceutical treatments for Alzheimer's disease (AD), the most common etiology of dementia, heralds the beginning of precision medicine in this field. However, their implementation will challenge an already over-burdened healthcare systems. There is a need for innovative digital solutions that can drive the related clinical pathways and optimize and personalize care delivery. Public-private partnerships are ideal vehicles to tackle these challenges. Here we describe the Innovative Health Initiative (IHI) public-private partnership project PROMINENT that has been initiated by connecting leading dementia researchers, medical professionals, dementia patients and their care partners with the latest innovative health technologies using a precision medicine based digital platform. The project builds upon the knowledge and already implemented digital tools from several collaborative initiatives that address new models for early detection, diagnosis, and monitoring of AD and other neurodegenerative disorders. The project aims to provide support to improvement efforts to each aspect of the care pathway including diagnosis, prognosis, treatment, and data collection for real world evidence and cost effectiveness studies. Ultimately the PROMINENT project is expected to lead to cost-effective care and improved health outcomes.

The association of feeding difficulties and generic health-related quality of life among children born with esophageal atresia.

BACKGROUND: Children born with esophageal atresia experience feeding difficulties. This study investigates the association of feeding difficulties and generic health-related quality of life among children aged 2-7 and 8-17 years, born with esophageal atresia. METHODS: 108 families (n = 36 aged 2-7 years; n = 72 aged 8-17) answered a survey regarding difficulties in their child's mealtimes and a validated generic health-related quality of life instrument(PedsQL 4.0). Clinical data was collected from hospital records. The association of feeding difficulties and health-related quality of life was analysed trough Mann-Whitney U-test. Linear regression determined whether the number of concurrent feeding difficulties in the child decreased the health-related quality of life scores. P < 0.05 was considered significant. RESULTS: In children aged 2-7 and 8-17 years, to have a gastrostomy, to use a food infusion pump, need for energy-enriched food and eating small portions were respectively significantly associated with lower total health-related quality of life scores in the parent-reports (p < 0.05). Most of the feeding difficulties had a negative significant relationship with the domains of physical and social functioning. Additionally, in the older age group, long mealtimes and adult mealtime supervision were associated with lower scores in both child and parent reports. In both age groups, an increased number of feeding difficulties in the child decreased the total generic health-related quality of life scores (p < 0.01). CONCLUSION: Specific feeding difficulties are associated with low health-related quality of life among children with esophageal atresia. An increasing number of feeding difficulties is associated to decreasing health-related quality of life-scores. Further research is needed to understand these associations.

Estimating the Product Lifecycle Value of Trastuzumab Based on Registry Data in Sweden.

BACKGROUND AND OBJECTIVE: Trastuzumab was introduced in Sweden in 2000 for treatment of HER2-positive metastatic breast cancer (MBC) and later expanded to early breast cancer (EBC). The potential value of this innovative therapy was explored in economic evaluations; however, the extent to which these benefits were realised remains unknown. This study aims to estimate the lifecycle value of trastuzumab by combining randomised trial data with Swedish routine-care data. METHODS: Trastuzumab impact on costs and health outcomes was estimated with Markov models for MBC and EBC. Model inputs included progression/recurrence and breast cancer-related mortality data from international randomised clinical trials, and Sweden-specific non-breast cancer-related mortality, numbers treated, and costs and utilities based on data from National Registries and literature. Model predictions were validated by observed survival rates from the National Breast Cancer Registry. RESULTS: From 2000 to 2021, 3936 and 11,134 patients with HER2-positive MBC and EBC, respectively, were treated with trastuzumab, resulting in 25,844 life years and 13,436 per quality-adjusted life years (QALY) gained. Cost per QALY gained was lower in EBC (Swedish krona [SEK] 285,000/QALY) than MBC (SEK 554,000/QALY). The net-monetary value delivered (excluding drug costs) was SEK 13.714 billion, and society retained 62% of this. The modelled survival in trastuzumab-treated patients with EBC matched closely with actually observed survival in registry data. CONCLUSION: Trastuzumab provided substantial population-level health benefits for patients and society, with favourable cost effectiveness in MBC and EBC. There is some uncertainty around the magnitude of these benefits, mainly due to missing data on health outcomes and number of treated patients with MBC.

The affordability of lecanemab, an amyloid-targeting therapy for Alzheimer's disease: an EADC-EC viewpoint.

Lecanemab, an anti-amyloid antibody with effects on biomarker and clinical endpoints in early Alzheimer's Disease (AD), was granted accelerated approval by the FDA in 2023 and regulatory review in Europe is ongoing. We estimate the population potentially eligible for treatment with lecanemab in the 27 EU countries to 5.4 million individuals. Treatment costs would exceed 133 billion EUR per year if the drug is priced similarly as in the United States, amounting to over half of the total pharmaceutical expenditures in the EU. This pricing would be unsustainable; the ability to pay for high-priced therapies varies substantially across countries. Pricing similarly to what has been announced for the United States may place the drug out of reach for patients in some European countries. Disparities in access to novel amyloid-targeting agents may further deepen the inequalities across Europe in health outcomes. As representatives of the European Alzheimer's Disease Consortium Executive Committee, we call for pricing policies that allow eligible patients across Europe to access important innovations, but also continued investments in research and development. Infrastructure to follow up the usage of new therapies in routine care and new payment models may be needed to address affordability and inequalities in patient access.

Estimating treatment effects on health utility scores for patients living with migraine: a post hoc analysis of the DELIVER trial.

BACKGROUND: This post hoc analysis aimed to estimate eptinezumab's therapeutic effect on health utilities and determined to which extent monthly migraine days (MMDs) explain changes in health utilities. RESEARCH DESIGN/METHODS: DELIVER, a randomized, double-blind, placebo-controlled phase 3b trial (NCT04418765), investigated eptinezumab efficacy and safety in patients with 2-4 prior migraine treatment failures. Regression analysis explored the relationship between utility scores and MMDs, with eptinezumab treatment as a covariate along with MMDs to identify any MMD-independent effect on utilities. Path analysis quantified eptinezumab's impact as mediated through MMD reduction. RESULTS: The base case model showed that each reduction in MMD was associated with a mean utility score increase (0.0189; 95% CI: 0.0180, 0.0198; P < 0.001). Mean utility score was generally higher for eptinezumab versus placebo, justifying addition of treatment effect to the base case model. Patients administered eptinezumab had on average 0.0562 (95% CI: 0.0382, 0.0742; P < 0.001) higher utility versus placebo when controlling for number of MMDs. From path analysis, MMD reduction resulting from eptinezumab treatment accounted for 53% additional utility gain observed in patients. CONCLUSIONS: Changes in MMDs alone inadequately captured migraine's impact on patient utility, as there was also a positive eptinezumab-driven, treatment-specific impact on utility score. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT04418765).

Effect of mortality in cost-effectiveness modeling of disease-modifying treatment for Alzheimer's disease.

INTRODUCTION: We examined (1) the magnitude of mortality attributed to Alzheimer's disease (AD), and (2) the effect of mortality in cost-effectiveness modeling of hypothetical disease-modifying treatment (DMT) in AD. METHOD: Data were derived from Swedish Dementia Registry (N = 39,308). Mortality was analyzed with survival analysis and multinomial logistic regression. A Markov microsimulation model was used to model the cost effectiveness of DMT using routine care as a comparator. Three scenarios were simulated: (1) indirect effect, (2) no effect on overall mortality, (3) indirect effect on AD-related mortality. RESULTS: Overall mortality increased with cognitive decline, age, male sex, number of medications used, and lower body mass index. Nearly all cause-specific mortality was associated with cognitive decline. DMT increased survival by 0.35 years in scenario 1 and 0.14 years in scenario 3. DMT with no mortality effect is the least cost effective. DISCUSSION: The results provide key mortality estimates and demonstrate influences on the cost effectiveness of DMT. Highlights: We describe cause-specific mortality in relation to disease severity in Alzheimer's disease (AD).We model different assumptions of disease-modifying treatment (DMT) on AD survival.DMT was the least cost effective when assuming no effect on AD survival.Cost effectiveness is mainly influenced by the relative cost of staying in each disease state.

A glycan epitope correlates with tau in serum and predicts progression to Alzheimer's disease in combination with APOE4 allele status.

INTRODUCTION: There is an urgent need for novel blood biomarkers for the detection of Alzheimer's disease (AD). We previously showed that levels of the bisecting N-acetylglucosamine glycan epitope was elevated in cerebrospinal fluid in AD. However, its diagnostic value in blood is unknown. METHODS: We analyzed blood levels of bisecting N-acetylglucosamine and total tau in a retrospective cohort of 233 individuals. Progression to AD was compared between the groups using Cox regression. The predictive value of the biomarkers was determined by logistic regression. RESULTS: Bisecting N-acetylglucosamine correlated with tau levels (p < 0.0001). Individuals with an intermediate tau/bisecting N-acetylglucosamine ratio had elevated AD risk (hazard ratio = 2.06, 95% confidence interval [CI]: 1.18-3.6). Moreover, a combined model including tau/bisecting N-acetylglucosamine ratio, apolipoprotein E (APOE) ε4 status, and Mini-Mental State Examination score predicted future AD (area under the curve = 0.81, 95% CI: 0.68-0.93). DISCUSSION: Bisecting N-acetylglucosamine in combination with tau is a valuable blood biomarker for predicting AD.

The value of maintaining cognition in patients with mild cognitive impairment: The innovation headroom and potential cost-effectiveness of roflumilast.

INTRODUCTION: Early health-technology assessment can support discussing scarce resource allocation among stakeholders. We explored the value of maintaining cognition in patients with mild cognitive impairment (MCI) by estimating: (1) the innovation headroom and (2) the potential cost effectiveness of roflumilast treatment in this population. METHODS: The innovation headroom was operationalized by a fictive 100% efficacious treatment effect, and the roflumilast effect on memory word learning test was assumed to be associated with 7% relative risk reduction of dementia onset. Both were compared to Dutch setting usual care using the adapted International Pharmaco-Economic Collaboration on Alzheimer's Disease (IPECAD) open-source model. RESULTS: The total innovation headroom expressed as net health benefit was 4.2 (95% bootstrap interval: 2.9-5.7) quality-adjusted life years (QALYs). The potential cost effectiveness of roflumilast was k€34 per QALY. DISCUSSION: The innovation headroom in MCI is substantial. Although the potential cost effectiveness of roflumilast treatment is uncertain, further research on its effect on dementia onset is likely valuable.

The worldwide costs of dementia in 2019.

INTRODUCTION: Dementia is a leading cause of death and disability globally. Estimating total societal costs demonstrates the wide impact of dementia and its main direct and indirect economic components. METHODS: We constructed a global cost model for dementia, presenting costs as cumulated global and regional costs. RESULTS: In 2019, the annual global societal costs of dementia were estimated at US $1313.4 billion for 55.2 million people with dementia, corresponding to US $23,796 per person with dementia. Of the total, US $213.2 billion (16%) were direct medical costs, US $448.7 billion (34%) direct social sector costs (including long-term care), and US $651.4 billion (50%) costs of informal care. DISCUSSION: The huge costs of dementia worldwide place enormous strains on care systems and families alike. Although most people with dementia live in low- and middle-income countries, highest total and per-person costs are seen in high-income countries. HIGHLIGHTS: Global economic costs of dementia were estimated to reach US $1313.4 in 2019. Sixty-one percent of people with dementia live in low-and middle-income countries, whereas 74% of the costs occur in high-income countries. The impact of informal care accounts for about 50% of the global costs. The development of a long-term care infrastructure is a great challenge for low-and middle-income countries. There is a great need for more cost studies, particularly in low- and middle-income countries. Discussions of a framework for global cost comparisons are needed.

Prevalence of Mental Health Problems, Associated Factors, and Health-Related Quality of Life in Children with Long-Gap Esophageal Atresia in Sweden.

BACKGROUND: Children with long-gap esophageal atresia (LGEA) face a high risk of digestive and respiratory morbidity, but their mental health outcomes have not been investigated. We aimed to identify the prevalence of mental health problems in children with LGEA, associated factors and health-related quality of life (HRQOL). METHODS: Twenty-six children with LGEA aged 3-17 were recruited nationwide in Sweden. One of their parents and adolescents aged 11-17 completed information on the child's mental health (Strength and Difficulties Questionnaire), generic (PedsQL 4.0) and condition-specific HRQOL (EA-QOL). Parents gave information on current child symptomatology. Mental health level was determined using validated norms; abnormal≥90 percentile/borderline≥80 percentile/normal. Elevated levels were considered borderline/abnormal. Data were analyzed using descriptives, correlation and Mann-Whitney-U test. Significance level was p < 0.05. RESULTS: Twelve children with LGEA aged 3-17 (46%) had elevated scores of ≥1 mental health domain in parent-reports, whereas 2 adolescents (15%) in self-reports. In parent-reports, 31% of the children had elevated levels of peer relationship problems, with associated factors being child sex male (p = 0.037), airway infections (p = 0.002) and disturbed night sleep (p = 0.025). Similarly, 31% showed elevated levels of hyperactivity/inattention, and associated factors were male sex (p = 0.005), asthma (p = 0.028) and disturbed night sleep (p = 0.036). Elevated levels of emotional symptoms, seen in 20%, were related to swallowing difficulties (p = 0.038) and vomiting problems (p = 0.045). Mental health problems correlated negatively with many HRQOL domains (p < 0.05). CONCLUSIONS: Children with LGEA risk mental health difficulties according to parent-reports, especially peer relationship problems and hyperactivity/inattention, with main risk factors being male sex, airway problems and sleep disturbances. This should be considered in follow-up care and research, particularly since their mental health problems may impair HRQOL. LEVELS OF EVIDENCE: Prognosis study, LEVEL II.

The Costs of Dementia in Europe: An Updated Review and Meta-analysis.

BACKGROUND AND OBJECTIVE: The prevalence of dementia is increasing, while new opportunities for diagnosing, treating and possibly preventing Alzheimer's disease and other dementia disorders are placing focus on the need for accurate estimates of costs in dementia. Considerable methodological heterogeneity creates challenges for synthesising the existing literature. This study aimed to estimate the costs for persons with dementia in Europe, disaggregated into cost components and informative patient subgroups. METHODS: We conducted an updated literature review searching PubMed, Embase and Web of Science for studies published from 2008 to July 2021 reporting empirically based cost estimates for persons with dementia in European countries. We excluded highly selective or otherwise biased reports, and used a random-effects meta-analysis to produce estimates of mean costs of care across five European regions. RESULTS: Based on 113 studies from 17 European countries, the estimated mean costs for all patients by region were highest in the British Isles (73,712 EUR), followed by the Nordics (43,767 EUR), Southern (35,866 EUR), Western (38,249 EUR), and Eastern Europe and Baltics (7938 EUR). Costs increased with disease severity, and the distribution of costs over informal and formal care followed a North-South gradient with Southern Europe being most reliant on informal care. CONCLUSIONS: To our knowledge, this study represents the most extensive meta-analysis of the cost for persons with dementia in Europe to date. Though there is considerable heterogeneity across studies, much of this is explained by identifiable factors. Further standardisation of methodology for capturing resource utilisation data may further improve comparability of future studies. The cost estimates presented here may be of value for cost-of-illness studies and economic evaluations of novel diagnostic technologies and therapies for Alzheimer's disease.

Cost-effectiveness models for Alzheimer's disease and related dementias: IPECAD modeling workshop cross-comparison challenge.

INTRODUCTION: The credibility of model-based economic evaluations of Alzheimer's disease (AD) interventions is central to appropriate decision-making in a policy context. We report on the International PharmacoEconomic Collaboration on Alzheimer's Disease (IPECAD) Modeling Workshop Challenge. METHODS: Two common benchmark scenarios, for the hypothetical treatment of AD mild cognitive impairment (MCI) and mild dementia, were developed jointly by 29 participants. Model outcomes were summarized, and cross-comparisons were discussed during a structured workshop. RESULTS: A broad concordance was established among participants. Mean 10-year restricted survival and time in MCI in the control group ranged across 10 MCI models from 6.7 to 9.5 years and 3.4 to 5.6 years, respectively; and across 4 mild dementia models from 5.4 to 7.9 years (survival) and 1.5 to 4.2 years (mild dementia). DISCUSSION: The model comparison increased our understanding of methods, data used, and disease progression. We established a collaboration framework to assess cost-effectiveness outcomes, an important step toward transparent and credible AD models.