Hypoxia-induced activation of HIF-1alpha/IL-1beta axis in microglia promotes glioma progression via NF-κB-mediated upregulation of heparanase expression.

BACKGROUND: Glioma is a common tumor that occurs in the brain and spinal cord. Hypoxia is a crucial feature of the tumor microenvironment. Tumor-associated macrophages/microglia play a crucial role in the advancement of glioma. This study aims to illuminate the detailed mechanisms by which hypoxia regulates microglia and, consequently, influences the progression of glioma. METHODS: The glioma cell viability and proliferation were analyzed by cell counting kit-8 assay and 5-ethynyl-2'-deoxyuridine assay. Wound healing assay and transwell assay were implemented to detect glioma cell migration and invasion, respectively. Enzyme-linked immunosorbent assay was conducted to detect protein levels in cell culture medium. The protein levels in glioma cells and tumor tissues were evaluated using western blot analysis. The histological morphology of tumor tissue was determined by hematoxylin-eosin staining. The protein expression in tumor tissues was determined using immunohistochemistry. Human glioma xenograft in nude mice was employed to test the influence of hypoxic microglia-derived interleukin-1beta (IL-1ß) and heparanase (HPSE) on glioma growth in vivo. RESULTS: Hypoxic HMC3 cells promoted proliferation, migration, and invasion abilities of U251 and U87 cells by secreting IL-1ß, which was upregulated by hypoxia-induced activation of hypoxia inducible factor-1alpha (HIF-1α). Besides, IL-1ß from HMC3 cells promoted glioma progression and caused activation of nuclear factor-κB (NF-κB) and upregulation of HPSE in vivo. We also confirmed that IL-1ß facilitated HPSE expression in U251 and U87 cells by activating NF-κB. Hypoxic HMC3 cells-secreted IL-1ß facilitated the proliferation, migration, and invasion of U251 and U87 cells via NF-κB-mediated upregulation of HPSE expression. Finally, we revealed that silencing HPSE curbed the proliferation and metastasis of glioma in mice. CONCLUSION: Hypoxia-induced activation of HIF-1α/IL-1ß axis in microglia promoted glioma progression via NF-κB-mediated upregulation of HPSE expression.

Clinical Characterization of Veterans With Alzheimer Disease by Disease Severity in the United States.

PURPOSE: We aimed to examine the clinical characteristics of US veterans who underwent neurocognitive test score-based assessments of Alzheimer disease (AD) stage in the Veterans Affairs Healthcare System (VAHS). METHODS: Test dates for specific stages of AD were referenced as index dates to study behavioral and psychological symptoms of dementia (BPSD) and other patient characteristics related to utilization/work-up and time to death. PATIENTS: We identified veterans with AD and neurocognitive evaluations using the VAHS Electronic Health Record (EHR). RESULTS: Anxiety and sleep disorders/disturbances were the most documented BPSDs across all AD severity stages. Magnetic resonance imaging, neurology and psychiatry consultations, and neuropsychiatric evaluations were slightly higher in veterans with mild AD than in those at later stages. The overall average time to death from the first AD severity record was 5 years for mild and 4 years for moderate/severe AD. CONCLUSION: We found differences in clinical symptoms, healthcare utilization, and survival among the mild, moderate, and severe stages of AD. These differences are limited by the low documentation of BPSDs among veterans with test score-based AD stages. These data support the hypothesis that our cohorts represent coherent subgroups of patients with AD based on disease severity.

Prevalence of Mild Cognitive Impairment and Alzheimer's Disease Identified in Veterans in the United States.

Background: Diagnostic codes can be instrumental for case identification in Alzheimer's disease (AD) research; however, this method has known limitations and cannot distinguish between disease stages. Clinical notes may offer more detailed information including AD severity and can complement diagnostic codes for case identification. Objective: To estimate prevalence of mild cognitive impairment (MCI) and AD using diagnostics codes and clinical notes available in the electronic healthcare record (EHR). Methods: This was a retrospective study in the Veterans Affairs Healthcare System (VAHS). Health records from Veterans aged 65 years or older were reviewed during Fiscal Years (FY) 2010-2019. Overall, 274,736 and 469,569 Veterans were identified based on a rule-based algorithm as having at least one clinical note for MCI and AD, respectively; 201,211 and 149,779 Veterans had a diagnostic code for MCI and AD, respectively. During FY 2011-2018, likely MCI or AD diagnosis was defined by≥2 qualifiers (i.e., notes and/or codes)≥30 days apart. Veterans with only 1 qualifier were considered as suspected MCI/AD. Results: Over the 8-year study, 147,106 and 207,225 Veterans had likely MCI and AD, respectively. From 2011 to 2018, yearly MCI prevalence increased from 0.9% to 2.2%; yearly AD prevalence slightly decreased from 2.4% to 2.1%; mild AD changed from 22.9% to 26.8%, moderate AD changed from 26.5% to 29.1%, and severe AD changed from 24.6% to 30.7. Conclusions: The relative distribution of AD severities was stable over time. Accurate prevalence estimation is critical for healthcare resource allocation and facilitating patients receiving innovative medicines.

The Role of Mental Health Conditions in Early Detection and Treatment of Veterans With Alzheimer's Dementia.

INTRODUCTION: The benefits of early detection of Alzheimer's disease (AD) have become increasingly recognized. Veterans with mental health conditions (MHCs) may be less likely to receive a specific AD diagnosis compared to veterans without MHCs. We investigated whether rates of MHCs differed between veterans diagnosed with unspecified dementia (UD) vs. AD to better understand the role MHCs might play in establishing a diagnosis of AD. MATERIALS AND METHODS: This retrospective analysis (2015-2022) identified UD and AD with diagnostic code-based criteria. We determined the proportion of veterans with MHCs in UD vs. AD cohorts. Secondarily, we assessed the distribution of UD/AD diagnoses in veterans with and without MHCs. RESULTS: We identified 145,309 veterans with UD and 33,996 with AD. The proportion of each MHC was consistently higher in UD vs. AD cohorts: 41.4% vs. 33.2% (depression), 26.9% vs. 20.3% (post-traumatic stress disorder), 23.4% vs. 18.2% (anxiety), 4.3% vs. 2.1% (bipolar disorder), and 3.9% vs. 1.5% (schizophrenia). The UD diagnostic code was used in 84% of veterans with MHCs vs. 78% without MHCs (P < .001). CONCLUSIONS: Mental health conditions were more likely in veterans with UD vs. AD diagnoses; comorbid MHC may contribute to delayed AD diagnosis.

Assessing Quality of Life, Economic Burden, and Independence Across the Alzheimer's Disease Continuum Using Patient-Caregiver Dyad Surveys.

Background: Alzheimer's disease (AD) and mild cognitive impairment (MCI) have negative quality of life (QoL) and economic impacts on patients and their caregivers and may increase along the disease continuum from MCI to mild, moderate, and severe AD. Objective: To assess how patient and caregiver QoL, indirect and intangible costs are associated with MCI and AD severity. Methods: An on-line survey of physician-identified patient-caregiver dyads living in the United States was conducted from June-October 2022 and included questions to both patients and their caregivers. Dementia Quality of Life Proxy, the Care-related Quality of Life, Work Productivity and Activity Impairment, and Dependence scale were incorporated into the survey. Regression analyses investigated the association between disease severity and QoL and cost outcomes with adjustment for baseline characteristics. Results: One-hundred patient-caregiver dyads were assessed with the survey (MCI, n = 27; mild AD, n = 27; moderate AD, n = 25; severe AD, n = 21). Decreased QoL was found with worsening severity in patients (p < 0.01) and in unpaid (informal) caregivers (n = 79; p = 0.02). Dependence increased with disease severity (p < 0.01). Advanced disease severity was associated with higher costs to employers (p = 0.04), but not with indirect costs to caregivers. Patient and unpaid caregiver intangible costs increased with disease severity (p < 0.01). A significant trend of higher summed costs (indirect costs to caregivers, costs to employers, intangible costs to patients and caregivers) in more severe AD was observed (p < 0.01). Conclusions: Patient QoL and functional independence and unpaid caregiver QoL decrease as AD severity increases. Intangible costs to patients and summed costs increase with disease severity and are highest in severe AD.

Alzheimer's Disease Stage Transitions Among United States Veterans.

BACKGROUND: Alzheimer's disease (AD) and related dementias are progressive neurological disorders with stage-specific clinical features and challenges. An important knowledge gap is the "window of time" within which patients transition from mild cognitive impairment or mild AD to moderate or severe AD. Better characterization/establishment of transition times would help clinicians initiating treatments, including anti-amyloid therapy. OBJECTIVE: To describe cognitive test score-based AD stage transitions in Veterans with AD in the US Veterans Affairs Healthcare System (VAHS). METHODS: This retrospective analysis (2010-2019) identified Veterans with AD from the VAHS Electronic Health Record (EHR) notes. AD stage was based on Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), or Saint Louis University Mental Status (SLUMS) Examination scores in the EHR. RESULTS: We identified 296,519 Veterans with cognitive test-based AD staging. Over the 10-year study, the proportion of veterans with MMSE scores declined from 24.9% to 9.5% while those with SLUMS rose from 9.0% to 17.8%; and MoCA rose from 5.0% to 25.4%. The average forward transition times between each stage were approximately 2-4 years, whether assessed by MMSE, MoCA, or SLUMS. CONCLUSION: The average transition time for cognitive test-based assessments of initial cognitive decline, early-stage AD, and moderate/severe AD in the VAHS is 2-4 years. In view of the short window for introducing disease-modifying therapy and the significant benefits of early treatment of AD, our data suggest a critical need for treatment guidelines in the management of AD.

Prognostic significance of MALAT1 in clear cell renal cell carcinoma based on TCGA and GEO.

Long noncoding RNAs metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) can regulate tumorigenesis and progression of various cancers. However, there is little known about the tumor biology and regulatory mechanism of MALAT1 in clear cell renal cell carcinoma (ccRCC). The objective of this study was to evaluate the prognostic value and potential functions of MALAT1 in ccRCC based on the cancer genome atlas. Through bioinformatics research, we analyzed the expression of MALAT1 in ccRCC, and the relationship with clinicopathological features, overall survival and infiltration of immune cells, and established the prognostic models. The results showed that MALAT1 was highly expressed in ccRCC tissues and predicted poor ccRCC patient outcome. The expression level of MALAT1 was significantly correlated with histologic grade, pathologic grade, T stage, M stage. ROC curve showed that MALAT1 had a good diagnostic accuracy, area under the curve of 0.752. The univariate and multivariate cox regression analysis showed that high MALAT1 expression was an independent prognostic factor for overall survival in the cancer genome atlas (hazard ratio = 2.271, 95% confidence interval: 1.435-3.593, P < .001). Gene set enrichment analysis revealed that MALAT1 expression was associated with the DNA methylation, epigenetic regulation of gene expression signaling pathway. In addition, the prognostic models were established to predict 1-, 3- and 5-year survival. This study showed that high expression of MALAT1 might be a potential diagnostic and prognostic biomarker.

Rule-Based Identification of Individuals with Mild Cognitive Impairment or Alzheimer's Disease Using Clinical Notes from the United States Veterans Affairs Healthcare System.

BACKGROUND: Early identification of individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) is a clinical and research imperative. Use of diagnostic codes for MCI and AD identification has limitations. We used clinical notes to supplement diagnostic codes in the Veterans Affairs Healthcare System (VAHS) electronic health records (EHR) to identify and establish cohorts of Veterans recorded with MCI or AD. METHODS: Targeted keyword searches for MCI ("Mild cognitive impairment;" "MCI") and AD ("Alz*") were used to extract clinical notes from the VAHS EHR from fiscal year (FY) 2010 through FY 2019. Iterative steps of inclusion and exclusion were applied until searches achieved a positive predictive value ≥ 80%. MCI and AD cohorts were identified via clinical notes and/or diagnostic codes (i.e., including Veterans recorded by "Notes Only," "Notes + Code," or "Codes Only"). RESULTS: A total of 2,134,661 clinical notes from 339,007 Veterans met the iterative search criteria for MCI due to any cause and 4,231,933 notes from 572,063 Veterans met the iterative search criteria for AD. Over the 10-year study period, the number of clinical notes recording AD was generally stable, whereas the number for MCI more than doubled. More Veterans were identified for the MCI or AD cohorts via clinical notes than by diagnostic codes, particularly in the AD cohort. Among Veterans identified by having "Notes + Code" for MCI, the number first recorded by a code was lower than the number first recorded by a note until FY 2015 and then gradually became comparable after FY 2015. Among Veterans identified by having "Notes + Code" for AD, the number first recorded by a note was more than double the number first recorded by a code AD in each of the FYs. CONCLUSIONS: Clinical note-based identification captured more Veterans recorded with MCI and AD than diagnostic code-based identification.

Assessing out-of-pocket expenses and indirect costs for the Alzheimer disease continuum in the United States.

BACKGROUND: The societal costs of Alzheimer disease (AD) are considerable. Cost data stratified by cost category (direct and indirect) and AD severity in the United States are limited. OBJECTIVE: To describe out-of-pocket (OOP) expenses and indirect costs from unpaid caregiving and work impairment among patients with AD by severity and among patients with mild cognitive impairment (MCI) in a representative sample of the US population. METHODS: Data from the Health and Retirement Study (HRS) were used. HRS respondents were included if they reported an AD diagnosis or were considered as having MCI based on their cognitive performance. MCI and AD severity staging was performed using a crosswalk from results of the modified Telephone Interview of Cognitive Status to the Mini-Mental State Examination. OOP expenses were assessed along with indirect costs (costs to caregivers from providing unpaid help and costs to employers). Sensitivity analyses were performed by varying assumptions of caregiver employment, missed workdays, and early retirement. Patients with AD were stratified by nursing home status, type of insurance, and income level. All cost calculations applied sampling weights. RESULTS: A total of 18,786 patients were analyzed. Patients with MCI (n = 17,885) and AD (n = 901) were aged 67.8 ± 10.7 and 80.9 ± 9.3 years, were 55.7% and 63.3% female, and were 28.3% and 0.9% employed, respectively. OOP expenses per patient per month increased with AD severity, ranging from $420 in mild to $903 in severe AD but were higher in MCI ($554) than in mild AD. Indirect costs to employers were similar across the AD continuum ($197-$242). Costs from unpaid caregiving generally increased by disease severity, from $72 (MCI) to $1,298 (severe AD). Total OOP and indirect costs increased by disease severity, from $869 (MCI) to $2,398 (severe AD). Sensitivity analysis assuming nonworking caregivers and zero costs to employers decreased the total OOP and indirect costs by 32%-53%. OOP expenses were higher for patients with AD who had private insurance (P < 0.01), had higher incomes (P < 0.01), or were in nursing homes (P < 0.01). Indirect costs to caregivers were lower for patients with AD in nursing homes ($600 vs $1,372, P < 0.01). Total indirect costs were higher for patients with AD with lower incomes ($1,498 vs $1,136, P < 0.01) and for those not in nursing homes ($1,571 vs $799, P < 0.01). CONCLUSIONS: This study shows that OOP expenses and indirect costs increase with AD severity, OOP expenses increase with higher income, subscription of private insurance, and nursing home residency, and total indirect costs decrease with higher income and nursing home residency in the United States. DISCLOSURES This study was financially sponsored by Eisai. Drs Zhang and Tahami are employees of Eisai. Drs Chandak, Khachatryan, and Hummel are employees of Certara; Certara is a paid consultant to Eisai. The views expressed here are those of the authors and are not to be attributed to their respective affiliations. Laura De Benedetti, BSc, provided medical writing support to the manuscript; she is an employee of Certara.

A Systematic Review of Clinical Practice Guidelines for Alzheimer's Disease and Strategies for Future Advancements.

INTRODUCTION: Alzheimer's disease (AD) is a disease continuum from pathophysiologic, biomarker and clinical perspectives. With the advent of advanced technologies, diagnosing and managing patients is evolving. METHODS: A systematic literature review (SLR) of practice guidelines for mild cognitive impairment (MCI) and AD dementia was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). This systematic literature review (SLR) aimed to summarize current clinical practice guidelines for screening, testing, diagnosis, treatment and monitoring in the AD continuum. The results of this SLR were used to propose a way forward for practice guidelines given the possible introduction of biomarker-guided technology using blood- or plasma-based assays and disease-modifying treatments (DMTs) targeted for early disease. RESULTS: 53 clinical practice guidelines were identified, 15 of which were published since 2018. Screening for asymptomatic populations was not recommended. Biomarker testing was not included in routine diagnostic practice. There was no consensus on which neurocognitive tests to use to diagnose and monitor MCI or AD dementia. Pharmacologic therapies were not recommended for MCI, while cholinesterase inhibitors and memantine were recommended for AD treatment. DISCUSSION: The pre-2018 and post-2018 practice guidelines share similar recommendations for screening, diagnosis and treatment. However, once DMTs are approved, clinicians will require guidance on the appropriate use of DMTs in a clinical setting. This guidance should include strategies for identifying eligible patients and evaluating the DMT benefit-to-risk profile to facilitate shared decision-making among physicians, patients and care partners. CONCLUSION: Regular evidence-based updates of existing guidelines for the AD continuum are required over the coming decades to integrate rapidly evolving technologic and medical scientific advances and bring emerging approaches for management of early disease into clinical practice. This will pave the way toward biomarker-guided identification and targeted treatment and the realization of precision medicine for AD.

Predicting the Societal Value of Lecanemab in Early Alzheimer's Disease in Japan: A Patient-Level Simulation.

INTRODUCTION: Alzheimer's disease (AD), a neurodegenerative disorder that progresses from mild cognitive impairment (MCI) to dementia, is responsible for significant burden on caregivers and healthcare systems. In this study, data from the large phase III CLARITY AD trial were used to estimate the societal value of lecanemab plus standard of care (SoC) versus SoC alone against a range of willingness-to-pay (WTP) thresholds from a healthcare and societal perspective in Japan. METHODS: A disease simulation model was used to evaluate the impact of lecanemab on disease progression in early AD based on data from the phase III CLARITY AD trial and published literature. The model used a series of predictive risk equations based on clinical and biomarker data from the Alzheimer's Disease Neuroimaging Initiative and Assessment of Health Economics in Alzheimer's Disease II study. The model predicted key patient outcomes, including life years (LYs), quality-adjusted life years (QALYs), and total healthcare and informal costs of patients and caregivers. RESULTS: Over a lifetime horizon, patients treated with lecanemab plus SoC gained an additional 0.73 LYs compared with SoC alone (8.50 years vs. 7.77 years). Lecanemab, with an average treatment duration of 3.68 years, was found to be associated with a 0.91 increase in patient QALYs and a total increase of 0.96 when accounting for caregiver utility. The estimated value of lecanemab varied according to the WTP thresholds (JPY 5-15 million per QALY gained) and the perspective employed. From the narrow healthcare payer's perspective, it ranged from JPY 1,331,305 to JPY 3,939,399. From the broader healthcare payer's perspective, it ranged from JPY 1,636,827 to JPY 4,249,702, while from the societal perspective, it ranged from JPY 1,938,740 to JPY 4,675,818. CONCLUSION: The use of lecanemab plus SoC would improve health and humanistic outcomes with reduced economic burden for patients and caregivers with early AD in Japan.

Isoalantolactone mediates the degradation of BCR-ABL protein in imatinib-resistant CML cells by down-regulating survivin.

Isoalantolactone (Iso) is a bioactive lactone isolated from the root of Inula helenium L, which has been reported to have many pharmacological effects. To investigate the role and mechanism of isoalantolactone in chronic myeloid leukemia (CML), we first investigated isoalantolactone's anti-proliferative effects on imatinib-sensitive and imatinib-resistant CML cells by CCK8. Flow cytometry was used to detect isoalantolactone-induced cell apoptosis. Survivin was overexpressed in KBM5 and KBM5T315I cells using the lentivirus vector pSIN-3×flag-PURO. In KBM5 and KBM5T315I cells, shRNA was used to knockdown survivin. Cellular Thermal Shift Assay (CETSA) was used to detect the interaction between isoalantolactone and survivin. The ubiquitin of survivin induced by isoalantolactone was detected through immunoprecipitation. Quantitative polymerase-chain reaction (Q-PCR) and western blotting were used to detect the levels of mRNA and protein. Isoalantolactone inhibits the proliferation and promotes apoptosis of imatinib-resistant CML cells. Although isoalantolactone inhibits the proteins of BCR-ABL and survivin, it cannot inhibit survivin and BCR-ABL mRNA levels. Simultaneously, it was shown that isoalantolactone can degrade survivin protein by increasing ubiquitination. It was demonstrated that isoalantolactone-induced survivin mediated downregulation of BCR-ABL protein. It was also revealed that isoalantolactone triggered BCR-ABL protein degradation via caspase-3. Altogether, isoalantolactone inhibits survivin through the ubiquitin proteasome pathway, and mediates BCR-ABL downregulation in a caspase-3 dependent manner. These data suggest that isoalantolactone is a natural compound, which can be used as a potential drug to treat TKI-resistant CML.

Estimating Transition Probabilities Across the Alzheimer's Disease Continuum Using a Nationally Representative Real-World Database in the United States.

INTRODUCTION: Clinical Alzheimer's disease (AD) begins with mild cognitive impairment (MCI) and progresses to mild, moderate, or severe dementia, constituting a disease continuum that eventually leads to death. This study aimed to estimate the probabilities of transitions across those disease states. METHODS: We developed a mixed-effects multi-state Markov model to estimate the transition probabilities, adjusted for 5 baseline covariates, using the Health and Retirement Study (HRS) database. HRS surveys older adults in the United States bi-annually. Alzheimer states were defined using the modified Telephone Interview of Cognitive Status (TICS-m). RESULTS: A total of 11,292 AD patients were analyzed. Patients were 70.8 ± 9.0 years old, 54.9% female, and with 12.0 ± 3.3 years of education. Within 1 year from the initial state, the model estimated a higher probability of transition to the next AD state in earlier disease: 12.8% from MCI to mild AD and 5.0% from mild to moderate AD, but < 1% from moderate to severe AD. After 10 years, the probability of transition to the next state was markedly higher for all states, but still higher in earlier disease: 29.8% from MCI to mild AD, 23.5% from mild to moderate AD, and 5.7% from moderate to severe AD. Across all AD states, the probability of transition to death was < 5% after 1 year and > 15% after 10 years. Older age, fewer years of education, unemployment, and nursing home stay were associated with a higher risk of disease progression (p < 0.01). CONCLUSIONS: This analysis shows that the risk of progression is greater in earlier AD states, increases over time, and is higher in patients who are older, with fewer years of education, unemployed, or in a nursing home at baseline. The estimated transition probabilities can provide guidance for future disease management and clinical trial design optimization, and can be used to refine existing cost-effectiveness frameworks.

The epidemiology of mild cognitive impairment, Alzheimer's disease and related dementia in U.S. veterans.

INTRODUCTION: US veterans have a unique dementia risk profile that may be evolving over time. METHODS: Age-standardized incidence and prevalence of Alzheimer's disease (AD), AD and related dementias (ADRD), and mild cognitive impairment (MCI) was estimated from electronic health records (EHR) data for all veterans aged 50 years and older receiving Veterans Health Administration (VHA) care from 2000 to 2019. RESULTS: The annual prevalence and incidence of AD declined, as did ADRD incidence. ADRD prevalence increased from 1.07% in 2000 to 1.50% in 2019, primarily due to an increase in the prevalence of dementia not otherwise specified. The prevalence and incidence of MCI increased sharply, especially after 2010. The prevalence and incidence of AD, ADRD, and MCI were highest in the oldest veterans, in female veterans, and in African American and Hispanic veterans. DISCUSSION: We observed 20-year trends of declining prevalence and incidence of AD, increasing prevalence of ADRD, and sharply increasing prevalence and incidence of MCI.

Up-regulated oxidized USP2a can increase Mdm2-p60-p53 to promote cell apoptosis.

Mdm2 promotes the ubiquitination and degradation of p53, while Mdm2-p60 can bind to p53 and reduce the Mdm2-induced p53 ubiquitination to improve its stability. USP2a can deubiquitinate and stabilize Mdm2, whether USP2a can regulate Mdm2-p60 needs to be further confirmed and elucidated. We found that oxidative stress can up-regulate USP2a at the post-transcriptional level and induce USP2a to be oxidized by forming inter-subunit disulfide bonds. The oxidized USP2a is closely related with cell apoptosis. In apoptotic cells, oxidized USP2a has enhanced protein stability and further stabilizes Mdm2-p60 through deubiquitination, and the USP2a-Mdm2-p60-p53 axis plays a role in cell apoptosis. Altogether USP2a is oxygen sensitive, oxidized USP2a exerts apoptotic effects through the Mdm2-p60-p53 axis, which provides an experimental basis for regulating p53 apoptotic signaling by targeting USP2a.

A Path to Improved Alzheimer's Care: Simulating Long-Term Health Outcomes of Lecanemab in Early Alzheimer's Disease from the CLARITY AD Trial.

INTRODUCTION: Alzheimer's disease (AD), a progressive neurodegenerative disease, is the main cause of dementia and one of the leading causes of death for elderly people in the USA. Lecanemab is a humanized IgG1 monoclonal antibody targeting amyloid protofibrils for the treatment of early AD [i.e., mild cognitive impairment (MCI) or mild AD dementia]. In a recent 18-month phase III trial, using a double-blind, placebo-controlled design, lecanemab treatment led to reduced brain amyloid burden and significant improvements in cognitive and functional abilities in individuals with early AD. METHODS: An evidence-based patient-level disease simulation model was updated to estimate the long-term health outcomes of lecanemab plus standard of care (SoC) compared to SoC alone in patients with early AD and evidence of brain amyloid burden, using recent phase III trial data and published literature. The disease progression is described by changes in the underlying biomarkers of AD, including measures of amyloid and tau, and their connection to the clinical presentation of the disease assessed through various patient-level scales of cognition and function. RESULTS: Lecanemab treatment was estimated to slow the progression of AD to moderate and severe stages and reduce the time spent in these more advanced states. In individuals with early AD, lecanemab plus SoC was associated with a gain of 0.71 quality-adjusted life-years (QALYs), a 2.95-year delay in mean time to progression to AD dementia, a reduction of 0.11 years in institutional care, and an additional 1.07 years in community care as shown in the base-case study. Improved health outcomes were demonstrated with lecanemab treatment when initiated earlier based on age, disease severity, or tau pathology, resulting in estimated gains in QALYs ranging from 0.77 to 1.09 years, compared to 0.4 years in the mild AD dementia subset, as shown by the model. CONCLUSION: The study findings demonstrate the potential clinical value of lecanemab for individuals with early AD by slowing down disease progression and prolonging time in earlier stages of disease, which significantly benefits not only patients and caregivers but also society overall. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03887455.

Understanding Barriers Along the Patient Journey in Alzheimer's Disease Using Social Media Data.

INTRODUCTION: We speculated that social media data from Alzheimer's disease (AD) stakeholders (patients, caregivers, and clinicians) could identify barriers along the patient journey in AD, and that insights gained may help devise strategies to remove barriers, and ultimately improve the patient journey. METHODS: Our sample was drawn from a repository of social media posts extracted from 112 public sources between January 1998 and December 2021 using natural language processing text-mining algorithms. The patient journey was classified into three phases: (1) early signs/experiences (Early Signs); (2) screening/assessment/diagnosis (Screening); and (3) treatment/management (Treatment). In the Early Signs phase, issues/challenges derived from a conceptual AD identification framework (ADIF) were examined. In subsequent phases, behavioral/psychiatric challenges, access/barriers to health care, screening/diagnostic methods, and symptomatic treatments for AD were identified. Posts were classified by AD stakeholder type or disease stage, if possible. RESULTS: We identified 225,977 AD patient journey-related social media posts. Anxiety was a predominant issue/challenge in all patient journey phases. In the Screening and Treatment phases combined, access/barriers to care were described in 16% of posts; unwillingness/resistance to seeking care was a major barrier (≥ 75% of access-related posts across all stakeholders). Commonly identified structural barriers (e.g., affordability/cost, geography/transportation/distance) were more common in patient/caregiver posts than clinician posts. Among Screening-related posts, imaging/scans were commonly mentioned by all stakeholders; biomarkers were more commonly mentioned by patients than clinicians. Treatment-related concerns were identified in 17% of stakeholder-specified posts that named pharmacological agents/classes for the symptomatic management of AD. CONCLUSION: This descriptive analysis of out-of-clinic experiences reflected in AD social media posts found that unwillingness/resistance to seeking care was a key barrier, followed by structural barriers to health care, such as affordability/cost. Insights from the lived experiences of AD stakeholders are valuable and highlight the need to improve the patient journey in AD and ease patient and caregiver burden.

Clinical and Scientific Challenges to Effectiveness Studies Under Coverage with Evidence Development in Alzheimer's Disease.

The Centers for Medicare and Medicaid Services (CMS) has recently issued a national coverage determination for US Food and Drug Administration (FDA)-approved anti-amyloid monoclonal antibodies (mAbs) for the treatment of Alzheimer's disease (AD) under coverage with evidence development (CED). CED schemes are complex, costly, and challenging, and often fail to achieve intended objectives because of administrative and implementation issues. AD is a heterogeneous, progressive neurodegenerative disorder with complex care pathway that additionally presents scientific challenges related to the choice of study design and methods used in evaluating CED schemes. These challenges are herein discussed. Clinical findings from the US Veterans Affairs healthcare system help inform our discussion of specific challenges to CED-required effectiveness studies in AD.

Estimated Societal Value of Lecanemab in Patients with Early Alzheimer's Disease Using Simulation Modeling.

INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with memory, cognitive, and behavioral deficits, and brings significant economic burden on caregivers and healthcare systems. This study aims to estimate the long-term societal value of lecanemab plus standard of care (SoC) versus SoC alone, corresponding to a range of willingness-to-pay (WTP) thresholds based on the phase III CLARITY AD trial readouts from both the US payer and societal perspectives. METHODS: An evidence-based model was developed to simulate the effects of lecanemab on disease progression in early AD using interconnected predictive equations based on longitudinal clinical and biomarker data derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The model was informed with the results of the phase III CLARITY AD trial and published literature. Key model outcomes included patient life-years (LYs), quality-adjusted life-years (QALYs), and total costs of both the direct and indirect costs of patients and caregivers over a lifetime horizon. RESULTS: Patients treated with lecanemab plus SoC gained an additional 0.62 years of life versus SoC alone (6.23 years vs. 5.61 years). The mean time on lecanemab was 3.91 years, and the treatment was associated with an increase in patient QALYs of 0.61 and an increase in total QALYs of 0.64 when both patient and caregiver utilities were considered. The model estimated that the annual value of lecanemab for the US payer perspective was US$18,709-35,678 ($19,710-37,351 for societal perspective) at the WTP threshold of $100,000-200,000 per QALY gained, respectively. Scenario analyses of patient subgroups, time horizon, input sources, treatment stopping rules, and treatment dosing were conducted to explore the impact of alternative assumptions on the model results. CONCLUSION: The economic study suggested that lecanemab plus SoC would improve health and humanistic (quality of life) outcomes and reduce economic burden for patients and caregivers in early AD.

Therapeutic preference for Alzheimer's disease treatments: a discrete choice experiment with caregivers and neurologists.

BACKGROUND: Alzheimer's disease (AD) is a major global health crisis in need of more effective therapies. However, difficult choices to optimize value-based care will need to be made. While identifying preferred therapeutic attributes of new AD therapies is necessary, few studies have explored how preferences may vary between the stakeholders. In this study, the trade-offs among key attributes of amyloid plaque-lowering therapies for AD were assessed using a discrete choice experiment (DCE) and compared between caregivers and neurologists. METHODS: An initial pilot study was conducted to identify the potentially relevant features of a new therapy. The DCE evaluated seven drug attributes: clinical effects in terms of delay in AD progression over the standard of care (SOC), variation in clinical effects, biomarker response (achieving amyloid plaque clearance on PET scan), amyloid-related imaging abnormalities-edema (ARIA-E), duration of therapy, need for treatment titration as well as route, and frequency of drug administration. Respondents were then randomly presented with 12 choice sets of treatment options and asked to select their preferred option in each choice set. Hierarchical Bayesian regression modeling was used to estimate weighted preference attributes, which were presented as mean partial utility scores (pUS), with higher scores suggesting an increased preference. RESULTS: Both caregivers (n = 137) and neurologists (n = 161) considered clinical effects (mean pUS = 0.47 and 0.82) and a 5% incremental in ARIA-E (mean pUS = - 0.26 and - 0.52) to be highly impactful determinants of therapeutic choice. In contrast, variation in clinical effects (mean pUS = 0.12 and 0.14) and treatment duration (mean pUS = - 0.02 and - 0.13) were the least important characteristics of any new treatment. Neurologists' also indicated that subcutaneous drug delivery (mean pUS = 0.42 vs. 0.07) and administration every 4 weeks (mean pUS = 1.0 vs. 0.20) are highly desirable therapeutic features. Respondents were willing to accept up to a 9% increment in ARIA-E for one additional year of delayed progression. CONCLUSIONS: Caregivers and neurologists considered incremental clinical benefit over SOC and safety to be highly desirable qualities for a new drug that could clear amyloid plaques and delay clinical progression and indicated a willingness to accept incremental ARIA-E to achieve additional clinical benefits.