Psychometric and adherence considerations for high-frequency, smartphone-based cognitive screening protocols in older adults.

OBJECTIVE: The psychometric rigor of unsupervised, smartphone-based assessments and factors that impact remote protocol engagement is critical to evaluate prior to the use of such methods in clinical contexts. We evaluated the validity of a high-frequency, smartphone-based cognitive assessment protocol, including examining convergence and divergence with standard cognitive tests, and investigating factors that may impact adherence and performance (i.e., time of day and anticipated receipt of feedback vs. no feedback). METHODS: Cognitively unimpaired participants (N = 120, Mage = 68.8, 68.3% female, 87% White, Meducation = 16.5 years) completed 8 consecutive days of the Mobile Monitoring of Cognitive Change (M2C2), a mobile app-based testing platform, with brief morning, afternoon, and evening sessions. Tasks included measures of working memory, processing speed, and episodic memory. Traditional neuropsychological assessments included measures from the Preclinical Alzheimer's Cognitive Composite battery. RESULTS: Findings showed overall high compliance (89.3%) across M2C2 sessions. Average compliance by time of day ranged from 90.2% for morning sessions, to 77.9% for afternoon sessions, and 84.4% for evening sessions. There was evidence of faster reaction time and among participants who expected to receive performance feedback. We observed excellent convergent and divergent validity in our comparison of M2C2 tasks and traditional neuropsychological assessments. CONCLUSIONS: This study supports the validity and reliability of self-administered, high-frequency cognitive assessment via smartphones in older adults. Insights into factors affecting adherence, performance, and protocol implementation are discussed.

Compensatory strategy use in diverse older adults with subjective cognitive complaints.

OBJECTIVES: The current study aimed to evaluate the relationship between subjective cognitive complaints (SCC) and compensatory strategy (CS) use in a diverse sample of non-Latinx White (NLW), Black, and Latinx American older adults. METHOD: 807 older adults (Mage = 65.38, 62.7% female) were recruited through Amazon's Mechanical Turk (MTurk) and Qualtrics Panel to complete questionnaires on SCC and CS use. Kruskall-Wallis tests were used to evaluate differences in SCC across groups given non-normal distributions. Analysis of variance (ANOVA) was used to evaluate group differences in CS use. The PROCESS macro for SPSS was used to examine whether demographic factors moderated the relationship between SCC and CS use. RESULTS: NLWs reported higher levels of SCC and greater overall use of CS in comparison to Latinx and Black individuals. Several demographic and psychosocial factors including age, ethno-racial group, education, and anxiety level were found to be associated with CS use. Education was found to moderate the association between SCC and CS use. CONCLUSION: Inconsistent with prior studies, our study found that NLWs reported the highest levels of SCC. CS were used across all racial/ethnic groups, but the frequency of CS use may be impacted by education level. While all education groups increased their CS in response to higher levels of SCC, this increase was more substantial for those with lower levels of education. Future work should consider individuals' cultural and educational background when examining SCC and/or developing CS-based intervention for the aging population.

Longitudinal Predictors of Informant-Rated Everyday Function in Mild Cognitive Impairment.

OBJECTIVE: To examine predictors of informant-reported everyday functioning in mild cognitive impairment (MCI) and relations between everyday function and conversion to dementia. METHODS: Informants of participants (n = 2614) with mild cognitive impairment (MCI) were administered the Functional Activities Questionnaire (FAQ). Changes in dimensions of functional ability as determined by an exploratory factor analysis (EFA) were examined over 3 years and participant predictors of change were examined using multilevel modeling (MLM). RESULTS: The FAQ consisted of 3 factors, multistep, finance, and memory/orientation daily tasks. Impairment in memory/orientation tasks was significantly higher than impairment in multistep tasks. Worse functioning was associated with greater depression, worse memory, worse speed/EF, higher years of education and identifying as White. There was variability in some of these associations with different FAQ factors. Impairments in financial and memory/orientation daily tasks predicted follow-up conversion to dementia. CONCLUSIONS: Depression, speed/EF, and memory are consistently associated with domains of everyday functioning. Race, education, and age may be more variability associated with everyday functioning. Specific attention should be paid to subtle declines in the financial and memory/orientation domains as they may uniquely predict future dementia development. Depression may be a modifiable risk factor associated with functional impairment over time.

Beyond depression: examining the role of anxiety and anxiety sensitivity on subjective cognition and functioning in older adults.

OBJECTIVES: Subjective cognitive difficulties in the elderly may serve as potential risk-factors for future, objective decline and conversion to neurodegenerative disorders (e.g., mild cognitive impairment [MCI] and dementia). Though these subjective declines have been associated with depression, and to a lesser extent, anxiety, it is unknown if related constructs (e.g. anxiety sensitivity) and specific kinds of worries (e.g. worry about developing dementia, health anxiety) are related to subjective declines. The current study sought to examine if cognitive concerns related to anxiety sensitivity, dementia worry, and health anxiety added incremental validity beyond general symptoms of anxiety and depression in predicting subjective cognition and functioning in a sample of older adults. METHODS: Participants were 429 older adults who were at least 60 years old. Participants completed questionnaires on subjective cognition, subjective everyday function, anxiety, depression, anxiety sensitivity, dementia worry, and health anxiety via Qualtrics Panels. Hierarchical multiple regressions were conducted. RESULTS: Our variables of interest (anxiety sensitivity, dementia worry, and health anxiety) added significant variance in predicting subjective cognition and everyday function. Specifically, anxiety sensitivity was related to subjective cognition and functioning, while dementia worry and health anxiety were variably associated. CONCLUSION: Our results suggest that constructs related to anxiety and worry have a significant relationship with subjective cognition and function in older adults beyond general symptoms of depression and anxiety. Future work should examine if interventions and education may help to decrease anxiety sensitivity and worry about dementia respectively in older adults, which may in tern protect against future subjective declines.

A Combination of Chemotherapy and Oncolytic Virotherapy Sensitizes Colorectal Adenocarcinoma to Immune Checkpoint Inhibitors in a cDC1-Dependent Manner.

Immune checkpoint therapy has shown great promise in the treatment of cancers with a high mutational burden, such as mismatch repair-deficient colorectal carcinoma (dMMR CRC). However, many patients fail to respond to immune checkpoint therapy. Using a mouse model of dMMR CRC, we demonstrated that tumors can be further sensitized to immune checkpoint therapy by using a combination of low-dose chemotherapy and oncolytic HSV-1. This combination induced the infiltration of CD8+ and CD4+ T cells into the tumor and the upregulation of gene signatures associated with the chemoattraction of myeloid cell subsets. When combined with immune checkpoint therapy, the combination promoted the infiltration of activated type 1 conventional dendritic cells (cDC1s) into the tumor. Furthermore, we found this combination strategy to be dependent on cDC1s, and its therapeutic efficacy to be abrogated in cDC1-deficient Batf3-/- mice. Thus, we demonstrated that the adjuvanticity of dMMR CRCs can be improved by combining low-dose chemotherapy and oncolytic HSV-1 in a cDC1-dependent manner.

Social factors that predict cognitive decline in older African American adults.

OBJECTIVES: Projections from the United States Census Bureau suggest that the African American population may be the fastest growing race over the next 30 years and that they may be at the highest risk for developing dementia later in life. Various social factors have been shown to be associated with cognitive function and health outcomes. The present study aims to evaluate the relationship between social engagement and cognitive decline in a cohort of older African American adults. METHODS: We utilized multilevel modeling to examine the association between cognitive decline and social engagement in a sample of 617 older African American adults. RESULTS: Social activity was associated with global cognition, perceptual speed, perceptual orientation, and episodic memory over time. Loneliness was associated with better semantic memory performance over time. Perceived discrimination was associated with better semantic memory performance over time. Larger social network was associated with worse perceptual speed scores over time. CONCLUSIONS: Although our findings on loneliness and perceived discrimination over time were inconsistent with prior research, our findings on social activity and social network size over time were consistent with past literature and are thought to be due to positive social interactions providing a catalyst for cognitively stimulating activities. These results suggest that interventions designed to preserve cognition in African American older adults should incorporate adequate social activity. Furthermore, to maximize effectiveness, interventions should not necessarily focus on just expanding one's social network.

Combined Radionuclide Therapy and Immunotherapy for Treatment of Triple Negative Breast Cancer.

Triple negative breast cancer (TNBC) is an aggressive subtype of the disease with poor clinical outcomes and limited therapeutic options. Immune checkpoint blockade (CP) has surged to the forefront of cancer therapies with widespread clinical success in a variety of cancer types. However, the percentage of TNBC patients that benefit from CP as a monotherapy is low, and clinical trials have shown the need for combined therapeutic modalities. Specifically, there has been interest in combining CP therapy with radiation therapy where clinical studies primarily with external beam have suggested their therapeutic synergy, contributing to the development of anti-tumor immunity. Here, we have developed a therapeutic platform combining radionuclide therapy (RT) and immunotherapy utilizing a radiolabeled biomolecule and CP in an E0771 murine TNBC tumor model. Survival studies show that while neither monotherapy is able to improve therapeutic outcomes, the combination of RT + CP extended overall survival. Histologic analysis showed that RT + CP increased necrotic tissue within the tumor and decreased levels of F4/80+ macrophages. Flow cytometry analysis of the peripheral blood also showed that RT + CP suppressed macrophages and myeloid-derived suppressive cells, both of which actively contribute to immune escape and tumor relapse.

Examining Relationships between Multiple Self-Reported Sleep Measures and Gait Domains in Cognitively Healthy Older Adults.

BACKGROUND: Gait-related changes in older adulthood may be related to changes in cognition (e.g., executive functioning), and recent work suggests that different self-reported measures of sleep may be tied to contrasting aspects of executive functioning. However, the relationship between these self-reported sleep measures and gait domains has not been explored. Such an investigation would be useful in helping to determine which older adults might exhibit changes in gait as well as experience other gait-associated changes (e.g., increased fall risk). OBJECTIVE: To examine associations between different aspects of self-reported sleep and gait domains in a sample of cognitively healthy older adults. METHOD: A total of 423 older adults (mean age 69.9 years, range 50-92) completed self-report measures of sleep quality, daytime sleepiness, and sleep-related distress. The participants also completed an objective, electronic measure of both single-task and dual-task gait (i.e., GAITRite). Principal component analyses were used to elucidate the solution for each gait condition, and multiple linear regression was used to examine the contributions of sleep measures to variability in gait performance. RESULTS: A 5-component solution of the single-task condition and a 4-component solution of the dual-task condition were identified. Multiple linear regressions revealed that a poorer sleep quality was associated with greater single-task and dual-task asymmetry. Greater daytime sleepiness was associated with increased dual-task gait variability and postural control. After controlling for the effects of other facets of sleep, sleep-related distress was not associated with any gait domain. CONCLUSIONS: Among cognitively healthy older adults,sleep quality and daytime sleepiness, but not sleep-related distress, are associated with aspects of gait. Patients who report these symptoms should be assessed and monitored for possible changes in gait.

Assessment of anxiety in older adults: psychometric properties and relationships with self-reported functional impairment.

OBJECTIVE: The current study aimed to examine the psychometric properties of two geriatric anxiety measures: the Geriatric Anxiety Inventory (GAI) and the Geriatric Anxiety Scale (GAS). This study also aimed to determine the relationships of these measures with two measures of functional ability and impairment: the Barkley Functional Impairment Scale (BFIS) and the Everyday Cognition Scale (E-Cog). DESIGN: Confirmatory factor analyses (CFA) were used to analyze the factor structures of the GAI and GAS in older adults. Tests for dependent correlations were used to examine the relationship between anxiety scales and functioning. SETTING: Amazon's Mechanical Turk. PARTICIPANTS: 348 participants (aged 55-85, M= 62.75 (4.8), 66.5% female) with no history of psychosis or traumatic brain injury. RESULTS: CFAs supported the previously demonstrated bifactor solution for the GAI. For the GAS, the previously demonstrated three-factor model demonstrated a good-to-excellent fit. Given the high correlation between the cognitive and affective factors (r =.89), a bifactor solution was also tested. The bifactor model of the GAS was found to be primarily unidimensional. Tests for dependent correlations revealed that the GAS demonstrated stronger relationships with measures of self-reported functional impairment than the GAI. CONCLUSIONS: The current study provides further psychometric validation of the factor structure of two geriatric anxiety measures in an older adult sample. The results support previous work completed on the GAI and the GAS. The GAS was more strongly correlated with self-reported functional impairment than the GAI, which may reflect differences in content in the two measures.

Psychometric properties of the expanded version of the inventory of depression and anxiety symptoms (IDAS-II) in a sample of older adults.

Objective: Given the strong relationship often found between self-report measures of anxiety and depression, the Inventory of Depression and Anxiety Symptoms (IDAS) was created and then expanded (IDAS-II) to assess common and unique symptom dimensions of these emotional disorders. Limited research has focused on the use of the IDAS-II with older adults and the purpose of the current study was to provide data on the reliability and validity of the IDAS-II in this population.Method: A sample of 323 participants (age 55-80 years) were recruited online using Amazon's Mechanical Turk (MTurk). They completed the IDAS-II and several other self-report questionnaires of internalizing symptoms, including widely used measures developed specifically for older adults. Internal consistency and validity of the IDAS-II were examined.Results: The IDAS-II demonstrated marginal to excellent internal consistency (α = .68-.91). An exploratory factor analysis indicated three factors: Distress, Positive Mood, and Obsessions. The IDAS-II explained a large amount of variance in the other measures of depression and anxiety (ranging from 52% to 76%) and the IDAS-II Dysphoria scale significantly related to all of the other measures of depression and anxiety (ranging from r = .69 to r = .81).Conclusion: These results support the use of the IDAS-II with older adults as it has good convergent validity with other commonly used measures of depression and anxiety, including those commonly used in the assessment of older adults. Further research can use the IDAS-II with both younger and older adults to examine age-related changes in depression and anxiety symptoms.

Examining differences in neuropsychiatric symptom factor trajectories in empirically derived mild cognitive impairment subtypes.

OBJECTIVE: The aim of this study was to examine neuropsychiatric symptom (NPS) factor severity progression over time in empirically derived (ED) mild cognitive impairment (MCI) subtypes. METHODS: Participants in the Alzheimer's Disease Neuroimaging Initiative study diagnosed with MCI by Alzheimer's Disease Neuroimaging Initiative protocol using conventional clinical (CC) criteria (n = 788) were reclassified using cluster analysis as amnestic, dysnomic, dysexecutive MCI, or cluster-derived normal (CC-Normal) using empirical criteria. Cognitively normal (CN) participants (n = 207) were also identified. The Neuropsychiatric Inventory-Questionnaire (NPI-Q) was administered from baseline through 48-month follow-up. Exploratory factor analysis was completed to determine the NPI-Q factor structure at 6-month follow-up. Multilevel modeling was used to determine NPI-Q symptom severity factor and apathy symptom progression over time by cognitive subtype. RESULTS: The exploratory factor analysis revealed that the NPI-Q consisted of 2 factors: hyperactivity/agitation and mood symptoms. Using clinical and empirical criteria, all MCI groups were identified as having more severe hyperactivity/agitation symptoms than CN participants. However, only the amnestic MCI group identified using empirical criteria showed an increase in symptom severity over time relative to CN participants. Mood factor and apathy symptoms were found to be more severe in dysexecutive and amnestic groups in both models. Similarly, both models identified a significant worsening of mood and apathy symptoms over time for dysexecutive and amnestic groups relative to CN participants. CONCLUSIONS: This study provides further support that empirical criteria aid in examining the progression of clinical characteristics associated with MCI. Further, it helps to identify which MCI subtypes may be at higher risk for NPS progression.

Preparation of an 18 F-Labeled Hydrocyanine Dye as a Multimodal Probe for Reactive Oxygen Species.

Hydrocyanine dyes are sensitive "turn-on" type optical probes that can detect reactive oxygen species (ROS). We have developed a method to prepare an 18 F-labeled hydrocyanine dye as a multi-modal PET and optical "turn-on" probe. A commercially available near infrared (NIR) dye was modified with a fluorinated prosthetic group that did not alter its ROS sensing properties in the presence of superoxide and hydroxyl radicals. The 18 F-labeled analogue was produced using a single-step terminal fluorination procedure. Positron emission tomography (PET) imaging and quantitative in vivo biodistribution studies indicated this novel probe had remarkably different pharmacokinetics compared to the oxidized cyanine analogue. The chemistry reported enables the use of quantitative and dynamic PET imaging for the in vivo study of hydrocyanine dyes as ROS probes.

(125)I-Tetrazines and Inverse-Electron-Demand Diels-Alder Chemistry: A Convenient Radioiodination Strategy for Biomolecule Labeling, Screening, and Biodistribution Studies.

A convenient method to prepare radioiodinated tetrazines was developed, such that a bioorthogonal inverse electron demand Diels-Alder reaction can be used to label biomolecules with iodine-125 for in vitro screening and in vivo biodistribution studies. The tetrazine was prepared by employing a high-yielding oxidative halo destannylation reaction that concomitantly oxidized the dihydrotetrazine precursor. The product reacts quickly and efficiently with trans-cyclooctene derivatives. Utility was demonstrated through antibody and hormone labeling experiments and by evaluating products using standard analytical methods, in vitro assays, and quantitative biodistribution studies where the latter was performed in direct comparison to Bolton-Hunter and direct iodination methods. The approach described provides a convenient and advantageous alternative to conventional protein iodination methods that can expedite preclinical development and evaluation of biotherapeutics.

Medication management error types: Associations with mild cognitive impairment subtype.

Objective: Medication management errors are suspected to be prevalent among older adults with mild cognitive impairment (MCI). This study examined types of simulated medication-taking errors in cognitively normal older adults (CN; n = 131), single domain amnestic MCI (sdMCI, n = 91), and multi-domain MCI (mdMCI, n = 44). Errors were measured using the medication management ability assessment (MMAA). Methods: 266 participants seen for neuropsychological evaluation (94.4% White, 57.9% female, average age = 72, average education = 14 years) completed the MMAA (version 4.1), a performance-based task of medication management. Group differences in MMAA total scores, accuracy, and error types were evaluated using Kruskall-Wallis H tests. This study was the first to explore a newly operationalized error, perseverations, caused by taking a specific dose ≥2 times during the simulation. Results: CN and sdMCI groups had higher MMAA total scores than individuals with mdMCI, indicating better overall performance. The mdMCI group made a higher number of omission errors (missed pills) than other groups, but no differences were found for commission errors (extra pills). The sdMCI group made more perseverative errors compared to the CN group. Conclusions: Individuals with mdMCI made more simulated medication management errors than CN and sdMCI groups, indicating that they may be most vulnerable to difficulties in medication management. In contrast, sdMCI individuals were more likely to make perseverative errors, which may reflect a tendency towards overcompensation of memory loss. Future studies should assess whether MMAA performance is associated with patterns of real-world medication-taking in more diverse samples of older adults.

Cognitive dispersion is related to subtle objective daily functioning changes in older adults with and without cognitive impairment.

Early detection of cognitive and functional decline is difficult given that current tools are insensitive to subtle changes. The present study evaluated whether cognitive dispersion on neuropsychological testing improved prediction of objectively assessed daily functioning using unobtrusive monitoring technologies. Hierarchical linear regression was used to evaluate whether cognitive dispersion added incremental information beyond mean neuropsychological performance in the prediction of objectively assessed IADLs (i.e., computer use, pillbox use, driving) in a sample of 104 community-dwelling older adults without dementia (Mage = 74.59, 38.5% Female, 90.4% White). Adjusting for age, sex, education, and mean global cognitive performance, cognitive dispersion improved prediction of average daily computer use duration (R2 Δ = 0.100, F Change, p = 0.005), computer use duration variability (R2 Δ = 0.089, F Change p = 0.009), and average daily duration of nighttime driving (R2 Δ = 0.072, F Change p = 0.013). These results suggest cognitive dispersion may improve prediction of objectively assessed functional changes in older adults without dementia.

Serious mental illness is associated with elevated risk of hospital readmission in veterans with heart failure.

OBJECTIVE: Adults with serious mental illness (SMI) have high rates of cardiovascular disease, particularly heart failure, which contribute to premature mortality. The aims were to examine 90- and 365-day all-cause medical or surgical hospital readmission in Veterans with SMI discharged from a heart failure hospitalization. The exploratory aim was to evaluate 180-day post-discharge engagement in cardiac rehabilitation, an effective intervention for heart failure. METHODS: This study used administrative data from the Veterans Health Administration (VHA) and Centers for Medicare & Medicaid Services between 2011 and 2019. SMI status and medical comorbidity were assessed in the year prior to hospitalization. Cox proportional hazards models (competing risk of death) were used to evaluate the relationship between SMI status and outcomes. Models were adjusted for VHA hospital site, demographics, and medical characteristics. RESULTS: The sample comprised 189,767 Veterans of which 23,671 (12.5%) had SMI. Compared to those without SMI, Veterans with SMI had significantly higher readmission rates at 90 (16.1% vs. 13.9%) and 365 (42.6% vs. 37.1%) days. After adjustment, risk of readmission remained significant (90 days: HR: 1.07, 95% CI: 1.03, 1.11; 365 days: HR: 1.10, 95% CI: 1.07, 1.12). SMI status was not significantly associated with 180-day cardiac rehabilitation engagement (HR: 0.98, 95% CI: 0.91, 1.07). CONCLUSIONS: Veterans with SMI and heart failure have higher 90- and 365-day hospital readmission rates even after adjustment. There were no differences in cardiac rehabilitation engagement based on SMI status. Future work should consider a broader range of post-discharge interventions to understand contributors to readmission.

Disentangling the genetic underpinnings of neuropsychiatric symptoms in Alzheimer's disease in the Alzheimer's Disease Sequencing Project: Study design and methodology.

INTRODUCTION: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD). There are no effective treatments targeting these symptoms. METHODS: To facilitate identification of causative mechanistic pathways, we initiated an effort (NIH: U01AG079850) to collate, harmonize, and analyze all available NPS data (≈ 100,000 samples) of diverse ancestries with whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP). RESULTS: This study will generate a genomic resource for Alzheimer's disease with both harmonized whole-genome sequencing and NPS phenotype data that will be publicly available through NIAGADS. Primary analyses will (1) identify novel genetic risk factors associated with NPS in AD, (2) characterize the shared genetic architecture of NPS in AD and primary psychiatric disorders, and (3) assess the role of ancestry effects in the etiology of NPS in AD. DISCUSSION: Expansion of the ADSP to harmonize and refine NPS phenotypes coupled with the proposed core analyses will lay the foundation to disentangle the molecular mechanisms underlying these detrimental symptoms in AD in diverse populations. Highlights: Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer's disease (AD).There are no effective treatments targeting NPS in AD.The current effort aims to collate, harmonize, and analyze all NPS data from the Alzheimer's Disease Sequencing Project.Core analyses will identify underlying genetic factors and mechanistic pathways.The harmonized genomic and phenotypic data from this initiative will be available through National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site.

Lower odds of successful community discharge after medical hospitalization for Veterans with schizophrenia: A retrospective cohort study of national data.

Medical comorbidity, particularly cardiovascular diseases, contributes to high rates of hospital admission and early mortality in people with schizophrenia. The 30 days following hospital discharge represents a critical period for mitigating adverse outcomes. This study examined the odds of successful community discharge among Veterans with schizophrenia compared to those with major affective disorders and those without serious mental illness (SMI) after a heart failure hospital admission. Data for Veterans hospitalized for heart failure were obtained from the Veterans Health Administration (VHA) and Centers for Medicare & Medicaid Services between 2011 and 2019. Psychiatric diagnoses and medical comorbidities were assessed in the year prior to hospitalization. Successful community discharge was defined as remaining in the community without hospital readmission, death, or hospice for 30 days after hospital discharge. Logistic regression analyses adjusting for relevant factors were used to examine whether individuals with a schizophrenia diagnosis showed lower odds of successful community discharge versus both comparison groups. Out of 309,750 total Veterans in the sample, 7377 (2.4%) had schizophrenia or schizoaffective disorder and 32,472 (10.5%) had major affective disorders (bipolar disorder or recurrent major depressive disorder). Results from adjusted logistic regression analyses demonstrated significantly lower odds of successful community discharge for Veterans with schizophrenia compared to the non-SMI (Odds Ratio [OR]: 0.63; 95% Confidence Interval [CI]: 0.60, 0.66) and major affective disorders (OR: 0.65, 95%; CI: 0.62, 0.69) groups. Intervention efforts should target the transition from hospital to home in the subgroup of Veterans with schizophrenia.

Time to Dementia Diagnosis Among Veterans with Comorbid Insomnia and Depressive Episodes.

Background: Older adults with heart failure are at elevated risk of Alzheimer's disease and related dementias (AD/ADRD). Research suggests that insomnia and depressive episodes contribute somewhat dissociable impacts on risk for AD/ADRD in this patient population, although the temporal ordering of effects is unknown. Objective: This study examined time to dementia diagnosis among patients with comorbid insomnia and/or depressive episodes in an epidemiological sample. Methods: Secondary data analyses were conducted using a cohort study of 203,819 Veterans with a primary admission diagnosis of heart failure in 129 VA Medical Centers. Results: Patients with diagnoses of both insomnia and depressive episodes had the shortest time to a dementia diagnosis at both 1-year (Hazard ratio = 1.43, 95% CI [1.36, 1.51]) and 3-year follow-up time points (Hazard ratio = 1.40, 95% CI [1.34, 1.47]) versus patients with one or neither comorbidity. Conclusions: Individuals with both comorbidities had the shortest time to dementia onset. Screening for these comorbidities may help to identify patients at elevated risk of dementia who could benefit from enhanced monitoring or early intervention strategies for more rapid detection and management of dementia symptoms.

Oncolytic BHV-1 Is Sufficient to Induce Immunogenic Cell Death and Synergizes with Low-Dose Chemotherapy to Dampen Immunosuppressive T Regulatory Cells.

Immunogenic cell death (ICD) can switch immunologically "cold" tumors "hot", making them sensitive to immune checkpoint inhibitor (ICI) therapy. Many therapeutic platforms combine multiple modalities such as oncolytic viruses (OVs) and low-dose chemotherapy to induce ICD and improve prognostic outcomes. We previously detailed many unique properties of oncolytic bovine herpesvirus type 1 (oBHV) that suggest widespread clinical utility. Here, we show for the first time, the ability of oBHV monotherapy to induce bona fide ICD and tumor-specific activation of circulating CD8+ T cells in a syngeneic murine model of melanoma. The addition of low-dose mitomycin C (MMC) was necessary to fully synergize with ICI through early recruitment of CD8+ T cells and reduced infiltration of highly suppressive PD-1+ Tregs. Cytokine and gene expression analyses within treated tumors suggest that the addition of MMC to oBHV therapy shifts the immune response from predominantly anti-viral, as evidenced by a high level of interferon-stimulated genes, to one that stimulates myeloid cells, antigen presentation and adaptive processes. Collectively, these data provide mechanistic insights into how oBHV-mediated therapy modalities overcome immune suppressive tumor microenvironments to enable the efficacy of ICI therapy.