Feasibility of Water Therapy for Slowing Autosomal Dominant Polycystic Kidney Disease Progression.

BACKGROUND: In animal models of ADPKD, high water intake (HWI) decreases vasopressin secretion and slows disease progression, but the efficacy of HWI in human ADPKD is uncertain. METHODS: This exploratory, prospective, crossover study of ADPKD subjects (n=7) evaluated the hypothesis that HWI slows the rate of increase in height-adjusted total kidney volume (ht-TKV; a biomarker for ADPKD progression) and reduces pain. Subjects at high risk of ADPKD progression (i.e., Mayo Imaging Classifications 1C/1D) were evaluated during 6 months of usual water intake (UWI), followed by 12 months of HWI calculated to reduce urine osmolality (Uosm) to < 285 mOsm/kg. Measurements of Uosm, serum copeptin (secreted in equimolar amounts with vasopressin), MRI measurements of htTKV, and pain survey responses were compared between HWI and UWI. RESULTS: During HWI, mean 24-hour Uosm decreased compared to UWI (428 [398-432] mOsm/kg vs. 209 [190-223] mOsm/kg; p=0.01), indicating adherence to the protocol. Decreases during HWI also occurred in levels of serum copeptin (5.8±2.0 pmol/L to 4.2±1.6 pmol/L; p=0.03), annualized rate of increase in ht-TKV (6.8% [5.9 - 8.5] to 4.4% [3.0 - 5.0]; p<0.02), pain occurrence and pain interference during sleep (p<0.01). HWI was well tolerated. CONCLUSIONS: HWI in patients at risk of rapid progression of ADPKD slowed the rate of ht-TKV growth and reduced pain. This suggests that suppressing vasopressin levels by HWI provides an effective non-pharmacologic treatment of ADPKD.

Quantitative susceptibility mapping for detection of kidney stones, hemorrhage differentiation, and cyst classification in ADPKD.

BACKGROUND AND PURPOSE: The objective is to demonstrate feasibility of quantitative susceptibility mapping (QSM) in autosomal dominant polycystic kidney disease (ADPKD) patients and to compare imaging findings with traditional T1/T2w magnetic resonance imaging (MRI). METHODS: Thirty-three consecutive patients (11 male, 22 female) diagnosed with ADPKD were initially selected. QSM images were reconstructed from the multiecho gradient echo data and compared to co-registered T2w, T1w, and CT images. Complex cysts were identified and classified into distinct subclasses based on their imaging features. Prevalence of each subclass was estimated. RESULTS: QSM visualized two renal calcifications measuring 9 and 10 mm and three pelvic phleboliths measuring 2 mm but missed 24 calcifications measuring 1 mm or less and 1 larger calcification at the edge of the field of view. A total of 121 complex T1 hyperintense/T2 hypointense renal cysts were detected. 52 (43%) Cysts appeared hyperintense on QSM consistent with hemorrhage; 60 (49%) cysts were isointense with respect to simple cysts and normal kidney parenchyma, while the remaining 9 (7%) were hypointense. The presentation of the latter two complex cyst subtypes is likely indicative of proteinaceous composition without hemorrhage. CONCLUSION: Our results indicate that QSM of ADPKD kidneys is possible and uniquely suited to detect large renal calculi without ionizing radiation and able to identify properties of complex cysts unattainable with traditional approaches.

Primary biliary cholangitis drug evaluation and regulatory approval: Where do we go from here?

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of Ursodeoxycholic Acid (UDCA). Up to 40% of patients do not, however, respond adequately to UDCA and therefore still remain at risk of disease progression to cirrhosis. The introduction of Obeticholic acid (OCA) as second-line therapy for patients failing UDCA has improved outcomes for PBC patients. There remains, however, a need for better treatments for higher risk patients. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorisation for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcomes trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with OCA, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcomes trials when a licensed drug is commercially available. New PBC therapies in development such as the PPAR agonists, face even greater challenges in demonstrating outcomes benefit through randomized placebo-controlled studies once following conditional marketing authorisation, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognise the importance of Real-World Data in providing evidence of outcomes benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through Real World data collection.

Peripheral Blood Mononuclear Cell Gene Expression Associated with Pulmonary Microvascular Perfusion: The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease Study.

Rationale Chronic obstructive pulmonary disease (COPD) and emphysema are associated with endothelial damage and altered pulmonary microvascular perfusion. Molecular mechanisms underlying these changes are poorly understood in patients due, in part, to the inaccessibility of the pulmonary vasculature. Peripheral blood mononuclear cells (PBMC) interact with the pulmonary endothelium. Objective To test the association between gene expression in PBMCs and pulmonary microvascular perfusion in COPD. Methods The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited two independent samples of COPD cases and controls with 10 or more pack-years. In both samples, pulmonary microvascular blood flow, pulmonary microvascular blood volume (PMBV), and mean transit time were assessed on contrast-enhanced MRI, and PBMC gene expression was assessed by microarray. Additional replication was performed in a third sample with PMBV measures on contrast-enhanced, dual-energy CT. Differential expression analyses were adjusted for age, gender, race-ethnicity, educational attainment, height, weight, smoking status, and pack-years. Results The 79 participants in the discovery sample had mean age of 69±6 years, 44% were female, 25% were non-white, 34% were current smokers and 66% had COPD. There were large PBMC gene expression signatures associated with pulmonary microvascular perfusion traits, with several replicated in the replication sets with MRI (n=47) or dual-energy CT scan (n=157) measures. Many of the identified genes are involved in inflammatory processes, including NF-κB and chemokine signaling pathways. Conclusions PBMC gene expression in NF-κB, inflammatory and chemokine signaling pathways was associated pulmonary microvascular perfusion in COPD, potentially offering new targetable candidates for novel therapies.

Developing interventions to improve detection of depression in primary healthcare settings in rural Ethiopia.

BACKGROUND: The poor detection of depression in primary healthcare (PHC) in low- and middle-income countries continues to threaten the plan to scale up mental healthcare coverage. AIMS: To describe the process followed to develop an intervention package to improve detection of depression in PHC settings in rural Ethiopia. METHOD: The study was conducted in Sodo, a rural district in south Ethiopia. The Medical Research Council's framework for the development of complex interventions was followed. Qualitative interviews, observations of provider-patient communication, intervention development workshops and pre-testing of the screening component of the intervention were conducted to develop the intervention. RESULTS: A multicomponent intervention package was developed, which included (a) manual-based training of PHC workers for 10 days, adapted from the World Health Organization's Mental Health Gap Action Programme Intervention Guide, with emphasis on depression, locally identified depressive symptoms, communication skills, training by people with lived experience and active learning methods; (b) screening for culturally salient manifestations of depression, using a four-item tool; (c) raising awareness among people attending out-patient clinics about depression, using information leaflets and health education; and (d) system-level interventions, such as supportive supervision, use of posters at health facilities and a decision support mobile app. CONCLUSIONS: This contextualised, multicomponent intervention package may lead to meaningful impact on the detection of depression in PHC in rural Ethiopia and similar settings. The intervention will be pilot tested for feasibility, acceptability and effectiveness before its wider implementation.

"Problems you can live with" versus emergencies: how community members in rural Ethiopia contend with conditions requiring surgery.

BACKGROUND: 98% of people with surgical conditions living in low- and middle-income countries (LMICs) do not receive safe, timely and affordable surgical and anesthesia care. Research exploring barriers to receiving care has tended to be narrow in focus, often facility-based and ignoring the community beliefs, experiences and behaviours that will be an essential component of closing the gap in surgical care. Using qualitative methods, we captured diverse community perspectives in rural Ethiopia: exploring beliefs, perceptions, knowledge and experiences related to surgical conditions, with the overall aim of (re)constructing explanatory models. METHODS: Our study was nested within a community-based survey of surgical conditions conducted in the Butajira Health and Demographic Surveillance Site, southern Ethiopia, and a follow-up study of people accessing surgical care in two local hospitals. We carried out 24 semi-structured interviews. Participants were community members who needed but did/did not access surgical care, community-based healthcare workers and traditional bone-setters. Interviews were conducted in Amharic, audio-recorded, transcribed, and translated into English. We initially carried out thematic analysis and we recognized that emerging themes were aligned with Kleinman's explanatory models framework and decided to use this to guide the final stages of analysis. RESULTS: We found that community members primarily understood surgical conditions according to severity. We identified two categories: conditions you could live with and those which required urgent care, with the latter indicating a clear and direct path to surgical care whilst the former was associated with a longer, more complex and experimental pattern of help-seeking. Fear of surgery and poverty disrupted help-seeking, whilst community narratives based on individual experiences fed into the body of knowledge people used to inform decisions about care. CONCLUSIONS: We found explanatory models to be flexible, responsive to new evidence about what might work best in the context of limited community resources. Our findings have important implications for future research and policy, suggesting that community-level barriers have the potential to be responsive to carefully designed interventions which take account of local knowledge and beliefs.

Gd-EOB-DTPA enhanced MRI based radiomics combined with clinical variables in stratifying hepatic functional reserve in HBV infected patients.

PURPOSES: To evaluate radiomics from Gd-EOB-DTPA enhanced MR combined with clinical variables for stratifying hepatic functional reserve in hepatitis B virus (HBV) patients. METHODS: Our study included 279 chronic HBV patients divided 8:2 for training and test cohorts. Radiomics features were extracted from the hepatobiliary phase (HBP) MR images. Radiomics features were selected to construct a Rad-score which was combined with clinical parameters in two models differentiating hepatitis vs. Child-Pugh A and Child-Pugh A vs. B/C. Performances of these stratifying models were compared using area under curve (AUC). RESULTS: Rad-score alone discriminated hepatitis vs. Child-Pugh A with AUC = 0.890, 0.914 and Child-Pugh A vs. B/C with AUC = 0.862, 0.865 for the training and test cohorts, respectively. Model 1 [Rad-score + clinical parameters for hepatitis vs. Child-Pugh A] showed AUC = 0.978 for the test cohort, which was higher than ALBI [albumin-bilirubin] and MELD [model for end-stage liver disease], with AUCs of 0.716, 0.799, respectively (p < 0.001, < 0.001). Model 2 [Rad-score + clinical parameters for Child-Pugh A vs. B/C] showed AUC of 0.890 in the test cohort, which was similar to ALBI (AUC = 0.908, p = 0.760), and higher than MELD (AUC = 0.709, p = 0.018). CONCLUSION: Rad-score combined with clinical variables stratifies hepatic functional reserve in HBV patients.

Test Retest Reproducibility of Organ Volume Measurements in ADPKD Using 3D Multimodality Deep Learning.

RATIONALE AND OBJECTIVES: Following autosomal dominant polycystic kidney disease (ADPKD) progression by measuring organ volumes requires low measurement variability. The objective of this study is to reduce organ volume measurement variability on MRI of ADPKD patients by utilizing all pulse sequences to obtain multiple measurements which allows outlier analysis to find errors and averaging to reduce variability. MATERIALS AND METHODS: In order to make measurements on multiple pulse sequences practical, a 3D multi-modality multi-class segmentation model based on nnU-net was trained/validated using T1, T2, SSFP, DWI and CT from 413 subjects. Reproducibility was assessed with test-re-test methodology on ADPKD subjects (n = 19) scanned twice within a 3-week interval correcting outliers and averaging the measurements across all sequences. Absolute percent differences in organ volumes were compared to paired students t-test. RESULTS: Dice similarlity coefficient > 97%, Jaccard Index > 0.94, mean surface distance < 1 mm and mean Hausdorff Distance < 2 cm for all three organs and all five sequences were found on internal (n = 25), external (n = 37) and test-re-test reproducibility assessment (38 scans in 19 subjects). When averaging volumes measured from five MRI sequences, the model automatically segmented kidneys with test-re-test reproducibility (percent absolute difference between exam 1 and exam 2) of 1.3% which was better than all five expert observers. It reliably stratified ADPKD into Mayo Imaging Classification (area under the curve=100%) compared to radiologist. CONCLUSION: 3D deep learning measures organ volumes on five MRI sequences leveraging the power of outlier analysis and averaging to achieve 1.3% total kidney test-re-test reproducibility.

Size Matters: How to Characterize ADPKD Severity by Measuring Total Kidney Volume.

Following patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) has been challenging because serum biomarkers such as creatinine often remain normal until relatively late in the disease [...].

Clinical Quality Control of MRI Total Kidney Volume Measurements in Autosomal Dominant Polycystic Kidney Disease.

Total kidney volume measured on MRI is an important biomarker for assessing the progression of autosomal dominant polycystic kidney disease and response to treatment. However, we have noticed that there can be substantial differences in the kidney volume measurements obtained from the various pulse sequences commonly included in an MRI exam. Here we examine kidney volume measurement variability among five commonly acquired MRI pulse sequences in abdominal MRI exams in 105 patients with ADPKD. Right and left kidney volumes were independently measured by three expert observers using model-assisted segmentation for axial T2, coronal T2, axial single-shot fast spin echo (SSFP), coronal SSFP, and axial 3D T1 images obtained on a single MRI from ADPKD patients. Outlier measurements were analyzed for data acquisition errors. Most of the outlier values (88%) were due to breathing during scanning causing slice misregistration with gaps or duplication of imaging slices (n = 35), slice misregistration from using multiple breath holds during acquisition (n = 25), composing of two overlapping acquisitions (n = 17), or kidneys not entirely within the field of view (n = 4). After excluding outlier measurements, the coefficient of variation among the five measurements decreased from 4.6% pre to 3.2%. Compared to the average of all sequences without errors, TKV measured on axial and coronal T2 weighted imaging were 1.2% and 1.8% greater, axial SSFP was 0.4% greater, coronal SSFP was 1.7% lower and axial T1 was 1.5% lower than the mean, indicating intrinsic measurement biases related to the different MRI contrast mechanisms. In conclusion, MRI data acquisition errors are common but can be identified using outlier analysis and excluded to improve organ volume measurement consistency. Bias toward larger volume measurements on T2 sequences and smaller volumes on axial T1 sequences can also be mitigated by averaging data from all error-free sequences acquired.

Pulmonary emphysema subtypes defined by unsupervised machine learning on CT scans.

BACKGROUND: Treatment and preventative advances for chronic obstructive pulmonary disease (COPD) have been slow due, in part, to limited subphenotypes. We tested if unsupervised machine learning on CT images would discover CT emphysema subtypes with distinct characteristics, prognoses and genetic associations. METHODS: New CT emphysema subtypes were identified by unsupervised machine learning on only the texture and location of emphysematous regions on CT scans from 2853 participants in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), a COPD case-control study, followed by data reduction. Subtypes were compared with symptoms and physiology among 2949 participants in the population-based Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study and with prognosis among 6658 MESA participants. Associations with genome-wide single-nucleotide-polymorphisms were examined. RESULTS: The algorithm discovered six reproducible (interlearner intraclass correlation coefficient, 0.91-1.00) CT emphysema subtypes. The most common subtype in SPIROMICS, the combined bronchitis-apical subtype, was associated with chronic bronchitis, accelerated lung function decline, hospitalisations, deaths, incident airflow limitation and a gene variant near DRD1, which is implicated in mucin hypersecretion (p=1.1 ×10-8). The second, the diffuse subtype was associated with lower weight, respiratory hospitalisations and deaths, and incident airflow limitation. The third was associated with age only. The fourth and fifth visually resembled combined pulmonary fibrosis emphysema and had distinct symptoms, physiology, prognosis and genetic associations. The sixth visually resembled vanishing lung syndrome. CONCLUSION: Large-scale unsupervised machine learning on CT scans defined six reproducible, familiar CT emphysema subtypes that suggest paths to specific diagnosis and personalised therapies in COPD and pre-COPD.

Axillary Lymphadenopathy After a COVID-19 Vaccine Booster Dose: Time to Resolution on Ultrasound Follow-Up and Associated Factors.

BACKGROUND. Because administration of booster doses of COVID-19 vaccines is ongoing, radiologists are continuing to encounter COVID-19 vaccine-related axillary lymphadenopathy on imaging. OBJECTIVE. The purposes of this study were to assess time to resolution of COVID-19 vaccine-related axillary lymphadenopathy identified on breast ultrasound after administration of a booster dose and to assess factors potentially associated with time to resolution. METHODS. This retrospective single-institution study included 54 patients (mean age, 57 years) with unilateral axillary lymphadenopathy ipsilateral to the site of injection of a booster dose of messenger RNA COVID-19 vaccine visualized on ultrasound (whether an initial breast imaging examination or follow-up to prior screening or diagnostic breast imaging) performed between September 1, 2021, and December 31, 2022, and who underwent follow-up ultrasound examinations until resolution of lymphadenopathy. Patient information was extracted from the EMR. Univariable and multivariable linear regression analyses were used to identify predictors of time to resolution. Time to resolution was compared with that in a previously described sample of 64 patients from the study institution that was used to evaluate time to resolution of axillary lymphadenopathy after the initial vaccination series. RESULTS. Six of the 54 patients had a history of breast cancer, and two had symptoms related to axillary lymphadenopathy (axillary pain in both patients). Among the 54 initial ultrasound examinations showing lymphadenopathy, 33 were screening examinations and 21 were diagnostic examinations. Lymphadenopathy had resolved a mean of 102 ± 56 (SD) days after administration of the booster dose and 84 ± 49 days after the initial ultrasound showing lymphadenopathy. Age, vaccine booster type (Moderna vs Pfizer-BioNTech), and history of breast cancer were not significantly associated with time to resolution in univariable or multivariable analyses (all p > .05). Time to resolution after administration of a booster dose was significantly shorter than time to resolution after administration of the first dose in the initial series (mean, 129 ± 37 days) (p = .01). CONCLUSION. Axillary lymphadenopathy after administration of a COVID-19 vaccine booster dose has a mean time to resolution of 102 days, shorter than the time to resolution after the initial vaccination series. CLINICAL IMPACT. The time to resolution after administration of a booster dose supports the current recommendation for a follow-up interval of at least 12 weeks when vaccine-related lymphadenopathy is suspected.

A health systems intervention to strengthen the integration of tuberculosis and COVID-19 detection: Outcomes of a quasi-experimental study in a high burden tuberculosis district in KwaZulu Natal, South Africa.

OBJECTIVES: The adverse effects of the COVID-19 pandemic on tuberculosis (TB) detection have been well documented. Despite shared symptoms, guidance for integrated screening for TBand COVID-19 are limited, and opportunities for health systems strengthening curtailed by lockdowns. We partnered with a high TB burden district in KwaZulu-Natal, South Africa, to co-develop an integrated approach to assessing COVID-19 and TB, delivered using online learning and quality improvement, and evaluated its performance on TB testing and detection. METHODS: We conducted a mixed methods study incorporating a quasi-experimental design and process evaluation in 10 intervention and 18 control clinics. Nurses in all 28 clinics were all provided access to a four-session online course to integrate TB and COVID-19 screening and testing, which was augmented with some webinar and in-person support at the 10 intervention clinics. We estimated the effects of exposure to this additional support using interrupted time series Poisson regression mixed models. Process evaluation data comprised interviews before and after the intervention. Thematic coding was employed to provide explanations for effects of the intervention. RESULTS: Clinic-level support at intervention clinics was associated with a markedly higher uptake (177 nurses from 10 intervention clinics vs. 19 from 18 control clinics). Lack of familiarity with online learning, and a preference for group learning hindered the transition from face-to-face to online learning. Even so, any exposure to training was initially associated with higher rates of GeneXpert testing (adjusted incidence ratio [IRR] 1.11, 95% confidence interval 1.07-1.15) and higher positive TB diagnosis (IRR 1.38, 1.11-1.71). CONCLUSIONS: These results add to the knowledge base regarding the effectiveness of interventions to strengthen TB case detection during the COVID-19 pandemic. The findings support the feasibility of a shift to online learning approaches in low-resource settings with appropriate support and suggest that even low-intensity interventions are capable of activating nurses to integrate existing disease control priorities during pandemic conditions.

QSM Throughout the Body.

Magnetic materials in tissue, such as iron, calcium, or collagen, can be studied using quantitative susceptibility mapping (QSM). To date, QSM has been overwhelmingly applied in the brain, but is increasingly utilized outside the brain. QSM relies on the effect of tissue magnetic susceptibility sources on the MR signal phase obtained with gradient echo sequence. However, in the body, the chemical shift of fat present within the region of interest contributes to the MR signal phase as well. Therefore, correcting for the chemical shift effect by means of water-fat separation is essential for body QSM. By employing techniques to compensate for cardiac and respiratory motion artifacts, body QSM has been applied to study liver iron and fibrosis, heart chamber blood and placenta oxygenation, myocardial hemorrhage, atherosclerotic plaque, cartilage, bone, prostate, breast calcification, and kidney stone.

Effect of Averaging Measurements From Multiple MRI Pulse Sequences on Kidney Volume Reproducibility in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Total kidney volume (TKV) is an important biomarker for assessing kidney function, especially for autosomal dominant polycystic kidney disease (ADPKD). However, TKV measurements from a single MRI pulse sequence have limited reproducibility, ± ~5%, similar to ADPKD annual kidney growth rates. PURPOSE: To improve TKV measurement reproducibility on MRI by extending artificial intelligence algorithms to automatically segment kidneys on T1-weighted, T2-weighted, and steady state free precession (SSFP) sequences in axial and coronal planes and averaging measurements. STUDY TYPE: Retrospective training, prospective testing. SUBJECTS: Three hundred ninety-seven patients (356 with ADPKD, 41 without), 75% for training and 25% for validation, 40 ADPKD patients for testing and 17 ADPKD patients for assessing reproducibility. FIELD STRENGTH/SEQUENCE: T2-weighted single-shot fast spin echo (T2), SSFP, and T1-weighted 3D spoiled gradient echo (T1) at 1.5 and 3T. ASSESSMENT: 2D U-net segmentation algorithm was trained on images from all sequences. Five observers independently measured each kidney volume manually on axial T2 and using model-assisted segmentations on all sequences and image plane orientations for two MRI exams in two sessions separated by 1-3 weeks to assess reproducibility. Manual and model-assisted segmentation times were recorded. STATISTICAL TESTS: Bland-Altman, Schapiro-Wilk (normality assessment), Pearson's chi-squared (categorical variables); Dice similarity coefficient, interclass correlation coefficient, and concordance correlation coefficient for analyzing TKV reproducibility. P-value < 0.05 was considered statistically significant. RESULTS: In 17 ADPKD subjects, model-assisted segmentations of axial T2 images were significantly faster than manual segmentations (2:49 minute vs. 11:34 minute), with no significant absolute percent difference in TKV (5.9% vs. 5.3%, P = 0.88) between scans 1 and 2. Absolute percent differences between the two scans for model-assisted segmentations on other sequences were 5.5% (axial T1), 4.5% (axial SSFP), 4.1% (coronal SSFP), and 3.2% (coronal T2). Averaging measurements from all five model-assisted segmentations significantly reduced absolute percent difference to 2.5%, further improving to 2.1% after excluding an outlier. DATA CONCLUSION: Measuring TKV on multiple MRI pulse sequences in coronal and axial planes is practical with deep learning model-assisted segmentations and can improve TKV measurement reproducibility more than 2-fold in ADPKD. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

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.