Protective Effects of ß-Blockers on Bone in Older Adults with Dementia.

Increased ß-adrenergic receptor activity has been hypothesized to cause bone loss in those with dementia. We investigated the effect of long-term ß-blocker use on rate of bone loss in older adults with dementia. We used a linear mixed-effects model to estimate the relationship between long-term ß-blocker use and rate of bone loss in participants from the Health Aging and Body Composition study. Records of 1198 participants were analyzed, 44.7% were men. Among the men, 25.2% had dementia and 20.2% were on ß-blockers, while in the women, 22.5% had dementia and 16.6% received ß-blockers. In the 135 men with dementia, 23 were taking ß-blockers, while 15 of 149 women with dementia were using ß-blockers. In men with dementia, ß-blocker users had 0.00491 g/cm2 less bone mineral density (BMD) loss per year at the femoral neck (i.e., 0.63% less loss per year) than non-users (p < 0.05). No differences were detected in women with or without dementia and men without dementia. ß-blockers may be protective by slowing down bone loss in older men with dementia.

Deep learning to predict rapid progression of Alzheimer's disease from pooled clinical trials: A retrospective study.

The rate of progression of Alzheimer's disease (AD) differs dramatically between patients. Identifying the most is critical because when their numbers differ between treated and control groups, it distorts the outcome, making it impossible to tell whether the treatment was beneficial. Much recent effort, then, has gone into identifying RPs. We pooled de-identified placebo-arm data of three randomized controlled trials (RCTs), EXPEDITION, EXPEDITION 2, and EXPEDITION 3, provided by Eli Lilly and Company. After processing, the data included 1603 mild-to-moderate AD patients with 80 weeks of longitudinal observations on neurocognitive health, brain volumes, and amyloid-beta (Aß) levels. RPs were defined by changes in four neurocognitive/functional health measures. We built deep learning models using recurrent neural networks with attention mechanisms to predict RPs by week 80 based on varying observation periods from baseline (e.g., 12, 28 weeks). Feature importance scores for RP prediction were computed and temporal feature trajectories were compared between RPs and non-RPs. Our evaluation and analysis focused on models trained with 28 weeks of observation. The models achieved robust internal validation area under the receiver operating characteristic (AUROCs) ranging from 0.80 (95% CI 0.79-0.82) to 0.82 (0.81-0.83), and the area under the precision-recall curve (AUPRCs) from 0.34 (0.32-0.36) to 0.46 (0.44-0.49). External validation AUROCs ranged from 0.75 (0.70-0.81) to 0.83 (0.82-0.84) and AUPRCs from 0.27 (0.25-0.29) to 0.45 (0.43-0.48). Aß plasma levels, regional brain volumetry, and neurocognitive health emerged as important factors for the model prediction. In addition, the trajectories were stratified between predicted RPs and non-RPs based on factors such as ventricular volumes and neurocognitive domains. Our findings will greatly aid clinical trialists in designing tests for new medications, representing a key step toward identifying effective new AD therapies.

On the Optimal Diagnosis and the Evolving Role of Pimavanserin in Parkinson's Disease Psychosis.

Parkinson's disease (PD) is associated with the development of psychosis (PDP), including hallucinations and delusions, in more than half of the patient population. Optimal PD management must therefore involve considerations about both motor and non-motor symptoms. Often, clinicians fail to diagnosis psychosis in patients with PD and, when it is recognized, treat it suboptimally, despite the availability of multiple interventions. In this paper, we provide a summary of the current guidelines and clinical evidence for treating PDP with antipsychotics. We also provide recommendations for diagnosis and follow-up. Finally, an updated treatment algorithm for PDP that incorporates the use of pimavanserin, the only US FDA-approved drug for the treatment of PDP, was developed by extrapolating from a limited evidence base to bridge to clinical practice using expert opinion and experience. Because pimavanserin is only approved for the treatment of PDP in the US, in other parts of the world other recommendations and algorithms must be considered.

Mapping of Alzheimer's disease related data elements and the NIH Common Data Elements.

BACKGROUND: Alzheimer's Disease (AD) is a devastating disease that destroys memory and other cognitive functions. There has been an increasing research effort to prevent and treat AD. In the US, two major data sharing resources for AD research are the National Alzheimer's Coordinating Center (NACC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI); Additionally, the National Institutes of Health (NIH) Common Data Elements (CDE) Repository has been developed to facilitate data sharing and improve the interoperability among data sets in various disease research areas. METHOD: To better understand how AD-related data elements in these resources are interoperable with each other, we leverage different representation models to map data elements from different resources: NACC to ADNI, NACC to NIH CDE, and ADNI to NIH CDE. We explore bag-of-words based and word embeddings based models (Word2Vec and BioWordVec) to perform the data element mappings in these resources. RESULTS: The data dictionaries downloaded on November 23, 2021 contain 1,195 data elements in NACC, 13,918 in ADNI, and 27,213 in NIH CDE Repository. Data element preprocessing reduced the numbers of NACC and ADNI data elements for mapping to 1,099 and 7,584 respectively. Manual evaluation of the mapping results showed that the bag-of-words based approach achieved the best precision, while the BioWordVec based approach attained the best recall. In total, the three approaches mapped 175 out of 1,099 (15.92%) NACC data elements to ADNI; 107 out of 1,099 (9.74%) NACC data elements to NIH CDE; and 171 out of 7,584 (2.25%) ADNI data elements to NIH CDE. CONCLUSIONS: The bag-of-words based and word embeddings based approaches showed promise in mapping AD-related data elements between different resources. Although the mapping approaches need further improvement, our result indicates that there is a critical need to standardize CDEs across these valuable AD research resources in order to maximize the discoveries regarding AD pathophysiology, diagnosis, and treatment that can be gleaned from them.

Mitochondrial health, physical functioning, and daily affect: Bioenergetic mechanisms of dementia caregiver well-being.

OBJECTIVE: Chronic stress adversely affects mental and physical well-being. However, health outcomes vary among people experiencing the same stressor. Individual differences in physical and emotional well-being may depend on mitochondrial biology, as energy production is crucial for stress regulation. This study investigated whether mitochondrial respiratory capacity corresponds to individual differences in dementia spousal caregivers' mental and physical health. METHODS: Spousal caregivers of individuals with Alzheimer's disease and related dementias (N = 102, mean age = 71, 78% female, 83% White) provided peripheral blood samples and completed self-report questionnaires on quality of life, caregiver burden, and a 7-day affect scale. Multiple and mixed linear regression were used to test the relationship between mitochondrial biology and well-being. RESULTS: Spare respiratory capacity (b = 12.76, CI[5.23, 20.28 ], p = .001), maximum respiratory capacity (b = 8.45, CI [4.54, 12.35], p < .0001), and ATP-linked respiration (b = 10.11, CI [5.05, 15.18], p = .0001) were positively associated with physical functioning. At average (b = -2.23, CI [-3.64, -.82], p = .002) and below average (b = -4.96, CI [-7.22, 2.70], p < .0001) levels of spare respiratory capacity, caregiver burden was negatively associated with daily positive affect. At above average levels of spare respiratory capacity, caregiver burden was not associated with positive affect (p = .65). CONCLUSIONS: Findings suggest that better mitochondrial health is associated with better psychological and physical health - a pattern consistent with related research. These findings provide some of the earliest evidence that cellular bioenergetics are related to well-being.

Community exposure to armed conflict and subsequent onset of alcohol use disorder.

AIMS: To measure the independent consequences of community-level armed conflict beatings on alcohol use disorders (AUD) among males in Nepal during and after the 2000-2006 conflict. DESIGN: A population-representative panel study from Nepal, with precise measures of community-level violent events and subsequent individual-level AUD in males. Females were not included because of low AUD prevalence. SETTING: Chitwan, Nepal. PARTICIPANTS: Four thousand eight hundred seventy-six males from 151 neighborhoods, systematically selected and representative of Western Chitwan. All residents aged 15-59 were eligible (response rate 93%). MEASUREMENTS: Measures of beatings in the community during the conflict (2000-2006), including the date and distance away, were gathered through neighborhood reports, geo-location and official resources, then linked to respondents' life histories of AUD (collected in 2016-2018) using the Nepal-specific Composite International Diagnostic Interview with life history calendar. Beatings nearby predict the subsequent onset of AUD during and after the armed conflict. Data were analyzed in 2021-2022. FINDINGS: Cohort-specific, discrete-time models revealed that within the youngest cohort (born 1992-2001), those living in neighborhoods where armed conflict beatings occurred were more likely to develop AUD compared with those in other neighborhoods (odds ratio = 1.66; 95% confidence interval = 1.02-2.71). In this cohort, a multilevel matching analysis designed to simulate a randomized trial showed the post-conflict incidence of AUD for those living in neighborhoods with any armed conflict beatings was 9.5% compared with 5.3% in the matched sample with no beatings. CONCLUSIONS: Among male children living in Chitwan, Nepal during the 2000-2006 armed conflict, living in a neighborhood where armed conflict beatings occurred is associated with increased odds of developing subsequent alcohol use disorder. This association was independent of personal exposure to beatings and other mental disorders.

Implementation of a pharmacy-driven rapid bacteremia response program.

PURPOSE: This report describes a comprehensive pharmacy-driven rapid bacteremia response program. SUMMARY: This novel program positioned the pharmacy department at a large, community health system to receive and respond to critical microbiologic diagnostic testing results, 24/7/365. The program empowered pharmacists to provide centralized, comprehensive care including assessing blood culture Gram stain results, adjusting antibiotic therapy per protocol, ordering repeat blood cultures, analyzing and interpreting rapid molecular diagnostic test results, placing orders for contact isolation, and communicating antibiotic recommendations to the treatment team. In the first year after program implementation, 2,282 blood culture Gram stains and 2,046 rapid diagnostic test results were called in to the pharmacy department. The program reduced the median time to effective therapy in patients who did not already have active antimicrobial orders from over 10 hours to less than 1 hour. Based on the Gram stain results, antibiotics were started per protocol in 34.2% of patients. Based on the rapid molecular diagnostic test results, adjustments were made to antibiotic regimens in 55.7% of cases after discussion with a provider. Of these adjustments, 39.9% were for escalation of antibiotics and 37.7% were for de-escalation of antibiotics. CONCLUSION: By expanding the scope of pharmacy practice, barriers to optimizing clinical care were overcome.

Characterizing Treatment Non-responders vs. Responders in Completed Alzheimer's Disease Clinical Trials.

Alzheimer's disease (AD) patients have varying responses to AD drugs and there may be no single treatment for all AD patients. Trial after trial shows that identifying non-responsive and responsive subgroups and their corresponding moderators will provide better insights into subject selection and interpretation in future clinical trials. We aim to extensively investigate pre-treatment features that moderate treatment effect of Galantamine, Bapineuzumab, and Semagacestat from completed trial data. We obtained individual-level patient data from ten randomized clinical trials. Six Galantamine trials and two Bapineuzumab trials were from Yale University Open Data Access Project and two Semagacestat trials were from the Center for Global Clinical Research Data. We included a total of 10,948 subjects. The trials were conducted worldwide from 2001 to 2012. We estimated treatment effect using causal forest modeling on each trial. Finally, we identified important pre-treatment features that determine treatment efficacy and identified responsive or nonresponsive subgroups. As a result, patient's pre-treatment conditions that determined the treatment efficacy of Galantamine differed by dementia stages, but we consistently observed that non-responders in Galantamine trials had lower BMI (25 vs 28, P < .001) and increased ages (74 vs 68, P < .001). Responders in Bapineuzumab and Semagacestat trials had lower Aß42 levels (6.41 vs 6.53 pg/ml, P < .001) and smaller whole brain volumes (983.13 vs 1052.78 ml, P < .001). 6 'positive' treatment trials had subsets of patients who had, in fact, not responded. 4 "negative" treatment trials had subsets of patients who had, in fact, responded. This study suggests that analyzing heterogeneity in treatment effects in "positive" or "negative" trials may be a very powerful tool for identifying distinct subgroups that are responsive to treatments, which may significantly benefit future clinical trial design and interpretation.

Detection of prions in the urine of patients affected by sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: Currently, it is unknown whether infectious prions are present in peripheral tissues and biological fluids of patients affected by sporadic Creutzfeldt-Jakob disease (sCJD), the most common prion disorder in humans. This represents a potential risk for inter-individual prion infection. The main goal of this study was to evaluate the presence of prions in urine of patients suffering from the major subtypes of sCJD. METHODS: Urine samples from sCJD patients spanning the six major subtypes were tested. As controls, we used urine samples from people affected by other neurological or neurodegenerative diseases as well as healthy controls. These samples were analyzed blinded. The presence of prions was detected by a modified version of the PMCA technology, specifically optimized for high sensitive detection of sCJD prions. RESULTS: The PMCA assay was first optimized to detect low quantities of prions in diluted brain homogenates from patients affected by all subtypes of sCJD spiked into healthy urine. Twenty-nine of the 81 patients affected by sCJD analyzed in this study were positive by PMCA testing, whereas none of the 160 controls showed any signal. These results indicate a 36% sensitivity and 100% specificity. The subtypes with the highest positivity rate were VV1 and VV2, which combined account for about 15-20% of all sCJD cases, and no detection was observed in MV1 and MM2. INTERPRETATION: Our findings indicate that potentially infectious prions are secreted in urine of some sCJD patients, suggesting a possible risk for inter-individual transmission. Prion detection in urine might be used as a noninvasive preliminary screening test to detect sCJD.

Knowledge-guided Deep Temporal Clustering for Alzheimer's Disease Subtypes in Completed Clinical Trials.

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder with varied patient progression. We aim to test the hypothesis that AD patients can be categorized into subgroups based on differences in progression. We leveraged data from three randomized clinical trials (RCTs) to develop a knowledge-guided, deep temporal clustering (KG-DTC) framework for AD subtyping. This model combined autoencoders for contextual information capture, k-means clustering for representation formation, and clinical outcome classification for clinical knowledge integration. The derived representations, encompassing demographics, APOE genotype, cognitive assessments, brain volumes, and biomarkers, were clustered using the Gaussian Mixture Model to identify AD subtypes. Our novel KG-DTC framework was developed using placebo data from 2,087 AD patients across three solanezumab clinical trials (EXPEDITION, EXPEDITION2, and EXPEDITION3), achieving high performance in outcome prediction and clustering. The KG-DTC model demonstrated superior clustering structures, especially when combined with k-means clustering loss. External validation with independent clinical trial data showed consistent clustering results, with a 0.33 silhouette score for three clusters. The model's stability was confirmed through a leave-one-out approach, with an average adjusted Rand Index around 0.945. Three distinct AD subtypes were identified, each exhibiting unique patterns of cognitive function, neurodegeneration, and amyloid beta levels. Notably, Subtype 3 (S3) showed rapid cognitive decline across multiple clinical measures (e.g., 0.64 in S1 vs. -1.06 in S2 vs. 15.09 in S3 of average ADAS total change score, p<.001). This innovative approach offers promising insights for understanding variability in treatment outcomes and personalizing AD treatment strategies.

The Impact of Routine Vaccinations on Alzheimer's Disease Risk in Persons 65 Years and Older: A Claims-Based Cohort Study using Propensity Score Matching.

BACKGROUND: Accumulating evidence suggests that adult vaccinations can reduce the risk of developing Alzheimer's disease (AD) and Alzheimer's disease related dementias. OBJECTIVE: To compare the risk for developing AD between adults with and without prior vaccination against tetanus and diphtheria, with or without pertussis (Tdap/Td); herpes zoster (HZ); or pneumococcus. METHODS: A retrospective cohort study was performed using Optum's de-identified Clinformatics® Data Mart Database. Included patients were free of dementia during a 2-year look-back period and were≥65 years old by the start of the 8-year follow-up period. We compared two similar cohorts identified using propensity score matching (PSM), one vaccinated and another unvaccinated, with Tdap/Td, HZ, or pneumococcal vaccines. We calculated the relative risk (RR) and absolute risk reduction (ARR) for developing AD. RESULTS: For the Tdap/Td vaccine, 7.2% (n = 8,370) of vaccinated patients and 10.2% (n = 11,857) of unvaccinated patients developed AD during follow-up; the RR was 0.70 (95% CI, 0.68-0.72) and ARR was 0.03 (95% CI, 0.02-0.03). For the HZ vaccine, 8.1% (n = 16,106) of vaccinated patients and 10.7% (n = 21,417) of unvaccinated patients developed AD during follow-up; the RR was 0.75 (95% CI, 0.73-0.76) and ARR was 0.02 (95% CI, 0.02-0.02). For the pneumococcal vaccine, 7.92% (n = 20,583) of vaccinated patients and 10.9% (n = 28,558) of unvaccinated patients developed AD during follow-up; the RR was 0.73 (95% CI, 0.71-0.74) and ARR was 0.02 (95% CI, 0.02-0.03). CONCLUSION: Several vaccinations, including Tdap/Td, HZ, and pneumococcal, are associated with a reduced risk for developing AD.

An ontology-based approach for harmonization and cross-cohort query of Alzheimer's disease data resources.

BACKGROUND: In the United States, the National Alzheimer's Coordinating Center (NACC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) are two major data sharing resources for Alzheimer's Disease (AD) research. NACC and ADNI strive to make their data more FAIR (findable, interoperable, accessible and reusable) for the broader research community. However, there is limited work harmonizing and supporting cross-cohort interoperability of the two resources. METHOD: In this paper, we leverage an ontology-based approach to harmonize data elements in the two resources and develop a web-based query system to search patient cohorts across the two resources. We first mapped data elements across NACC and ADNI, and performed value harmonization for the mapped data elements with inconsistent permissible values. Then we built an Alzheimer's Disease Data Element Ontology (ADEO) to model the mapped data elements in NACC and ADNI. We further developed a prototype cross-cohort query system to search patient cohorts across NACC and ADNI. RESULTS: After manual review, we found 172 mappings between NACC and ADNI. These 172 mappings were further used to construct common concepts in ADEO. Our data element mapping and harmonization resulted in five files storing common concepts, variables in NACC and ADNI, mappings between variables and common concepts, permissible values of categorical type data elements, and coding inconsistency harmonization, respectively. Our cross-cohort query system consists of three core architectural elements: a web-based interface, an advanced query engine, and a backend MongoDB database. CONCLUSIONS: In this work, ADEO has been specifically designed to facilitate data harmonization and cross-cohort query of NACC and ADNI data resources. Although our prototype cross-cohort query system was developed for exploring NACC and ADNI, its backend and frontend framework has been designed and implemented to be generally applicable to other domains for querying patient cohorts from multiple heterogeneous data sources.

Do vaccinations influence the development of Alzheimer disease?

A growing literature supports a protective association between vaccines targeting an array of pathogens (e.g., influenza, pneumococcus, herpes zoster) and the risk of Alzheimer disease (AD). This article discusses the potential underlying mechanisms for this apparent protective effect of immunizations against infectious pathogens on the risk of AD; explores the basic and pharmacoepidemiologic evidence for this association, with particular attention paid to important methodological variations among the epidemiologic studies; and reviews the remaining uncertainties regarding the effects of anti-pathogen vaccines on Alzheimer disease and all-cause dementia, with recommendations for future directions to address those uncertainties.

Diagnosis of Respiratory Syncytial Virus in Adults Substantially Increases When Adding Sputum, Saliva, and Serology Testing to Nasopharyngeal Swab RT-PCR.

INTRODUCTION: Nearly all existing respiratory syncytial virus (RSV) incidence estimates are based on real-time polymerase chain reaction (RT-PCR) testing of nasal or nasopharyngeal (NP) swabs. Adding testing of additional specimen types to NP swab RT-PCR increases RSV detection. However, prior studies only made pairwise comparisons and the synergistic effect of adding multiple specimen types has not been quantified. We compared RSV diagnosis by NP swab RT-PCR alone versus NP swab plus saliva, sputum, and serology. METHODS: This was a prospective cohort study over two study periods (27 December 2021 to 1 April 2022 and 22 August 2022 to 11 November 2022) of patients aged ≥ 40 years hospitalized for acute respiratory illness (ARI) in Louisville, KY. NP swab, saliva, and sputum specimens were collected at enrollment and PCR tested (Luminex ARIES platform). Serology specimens were obtained at acute and convalescent timepoints (enrollment and 30-60-day visit). RSV detection rate was calculated for NP swab alone and for NP swab plus all other specimen type/test. RESULTS: Among 1766 patients enrolled, 100% had NP swab, 99% saliva, 34% sputum, and 21% paired serology specimens. RSV was diagnosed in 56 (3.2%) patients by NP swab alone, and in 109 (6.2%) patients by NP swab plus additional specimens, corresponding to a 1.95 times higher rate [95% confidence interval (CI) 1.62, 2.34]. Limiting the comparison to the 150 subjects with all four specimen types available (i.e., NP swab, saliva, sputum, and serology), there was a 2.60-fold increase (95% CI 1.31, 5.17) compared to NP swab alone (3.3% versus 8.7%). Sensitivities by specimen type were: NP swab 51%, saliva 70%, sputum 72%, and serology 79%. CONCLUSIONS: Diagnosis of RSV in adults was several-fold greater when additional specimen types were added to NP swab, even with a relatively low percentage of subjects with sputum and serology results available. Hospitalized RSV ARI burden estimates in adults based solely on NP swab RT-PCR should be adjusted for underestimation.

Social and Leisure Activities Predict Transitions in Cognitive Functioning in Older Mexican Adults: A Latent Transition Analysis of the Mexican Health and Aging Study.

OBJECTIVES: Mexico has a rapidly aging population at risk for cognitive impairment. Social and leisure activities may protect against cognitive decline in older adults. The benefits of these behaviors may vary by patterns of cognitive impairment. The objectives of this study were to identify latent states of cognitive functioning, model the incidence of transitions between these states, and investigate how social and leisure activities were associated with state transitions over a 6-year period in Mexican adults aged 60 and older. METHODS: We performed latent transition analyses to identify distinct cognitive statuses in the 2012 and 2018 waves of the Mexican Health and Aging Study (N = 9,091). We examined the transition probabilities between these states and their associations with social and leisure activities. RESULTS: We identified 4 cognitive statuses at baseline: normal cognition (43%), temporal disorientation (30%), perceptual-motor function impairment (7%), and learning and memory impairment (20%). Various social and leisure activities were associated with reduced odds of death and disadvantageous cognitive transitions, as well as increased odds of beneficial transitions. DISCUSSION: Mapping the effects of popular social and leisure activities onto common patterns in cognitive functioning may inform the development of more enjoyable and effective health-protective behavioral interventions.

Angiotensin-II stimulating vs. inhibiting antihypertensive drugs and the risk of Alzheimer's disease or related dementia in a large cohort of older patients with colorectal cancer.

Background: Several previous studies showed that patients who received angiotensin II-stimulating antihypertensive medications had a lower incident dementia rate than those angiotensin II-inhibiting antihypertensive users, but no study has been conducted in long-term cancer survivors. Objectives: To determine the risk of Alzheimer's disease (AD) and related dementia (ADRD) associated with the types of antihypertensive medications in a large cohort of survivors with colorectal cancer in 2007-2015 with follow-up from 2007 to 2016. Methods: We identified 58,699 men and women with colorectal cancer aged 65 or older from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database in 17 SEER areas in 2007-2015 with follow-up to 2016, who were free of any diagnosed ADRD at the baseline (within 12 months prior to and 12 months after the date of diagnosis for colorectal cancer). All patients who were defined as having hypertension by ICD diagnosis code or received antihypertensive drugs during this baseline 2-year period were classified into 6 groups based on whether they received angiotensin-II stimulating or inhibiting antihypertensive drugs. Results: Crude cumulative incidence rates of AD and ADRD were similar between those who received angiotensin II-stimulating antihypertensive medications (4.3% and 21.7%) and those receiving angiotensin II-inhibiting antihypertensive medications (4.2% and 23.5%). As compared to patients who received angiotensin II-stimulating antihypertensive drugs, those who received angiotensin II-inhibiting antihypertensives were significantly more likely to develop AD (adjusted hazard ratio: 1.15, 95% CI: 1.01-1.32), vascular dementias (1.27, 1.06-1.53), and total ADRD (1.21, 1.14-1.28) after adjusting for potential confounders. These results remained similar after adjusting for medication adherence and considering death as a competing risk. Conclusions: The risk of AD and ADRD in patients with hypertension who received angiotensin II-inhibiting antihypertensive medications was higher than in those receiving angiotensin II-stimulating antihypertensive drugs in patients with colorectal cancer.

Population-Based Mini-Mental State Examination Norms in Adults of Mexican Heritage in the Cameron County Hispanic Cohort.

BACKGROUND: Accurately identifying cognitive changes in Mexican American (MA) adults using the Mini-Mental State Examination (MMSE) requires knowledge of population-based norms for the MMSE, a scale which has widespread use in research settings. OBJECTIVE: To describe the distribution of MMSE scores in a large cohort of MA adults, assess the impact of MMSE requirements on their clinical trial eligibility, and explore which factors are most strongly associated with their MMSE scores. METHODS: Visits between 2004-2021 in the Cameron County Hispanic Cohort were analyzed. Eligible participants were ≥18 years old and of Mexican descent. MMSE distributions before and after stratification by age and years of education (YOE) were assessed, as was the proportion of trial-aged (50-85- year-old) participants with MMSE <24, a minimum MMSE cutoff most frequently used in Alzheimer's disease (AD) clinical trials. As a secondary analysis, random forest models were constructed to estimate the relative association of the MMSE with potentially relevant variables. RESULTS: The mean age of the sample set (n = 3,404) was 44.4 (SD, 16.0) years old and 64.5% female. Median MMSE was 28 (IQR, 28-29). The percentage of trial-aged participants (n = 1,267) with MMSE <24 was 18.6% overall and 54.3% among the subset with 0-4 YOE (n = 230). The five variables most associated with the MMSE in the study sample were education, age, exercise, C-reactive protein, and anxiety. CONCLUSION: The minimum MMSE cutoffs in most phase III prodromal-to-mild AD trials would exclude a significant proportion of trial-aged participants in this MA cohort, including over half of those with 0-4 YOE.

Feasibility, Acceptability, and Efficacy of Home-Based Transcranial Direct Current Stimulation on Pain in Older Adults with Alzheimer's Disease and Related Dementias: A Randomized Sham-Controlled Pilot Clinical Trial.

Although transcranial direct current stimulation (tDCS) is emerging as a convenient pain relief modality for several chronic pain conditions, its feasibility, acceptability, and preliminary efficacy on pain in patients with Alzheimer's disease and related dementias (ADRD) have not been investigated. The purpose of this pilot study was to assess the feasibility, acceptability, and preliminary efficacy of 5, 20-min home-based tDCS sessions on chronic pain in older adults with ADRD. We randomly assigned 40 participants to active (n = 20) or sham (n = 20) tDCS. Clinical pain intensity was assessed using a numeric rating scale (NRS) with patients and a proxy measure (MOBID-2) with caregivers. We observed significant reductions of pain intensity for patients in the active tDCS group as reflected by both pain measures (NRS: Cohen's d = 0.69, p-value = 0.02); MOBID-2: Cohen's d = 1.12, p-value = 0.001). Moreover, we found home-based tDCS was feasible and acceptable intervention approach for pain in ADRD. These findings suggest the need for large-scale randomized controlled studies with larger samples and extended versions of tDCS to relieve chronic pain on the long-term for individuals with ADRD.

Amyloid-Related Imaging Abnormalities: An Update.

Amyloid-related imaging abnormalities (ARIA) is a term introduced in 2010 to encompass a spectrum of MRI findings observed in patients receiving investigational anti-amyloid beta (Aß) immunotherapies for Alzheimer disease (AD). The entity can be broadly categorized into ARIA characterized by edema and effusion (ARIA-E) and ARIA characterized by microhemorrhages and superficial siderosis (ARIA-H). ARIA typically occurs early in the treatment course and has a higher incidence in patients who are apolipoprotein E ε4 allele carriers. ARIA-E has an additional dose dependence, with higher incidence in patients receiving higher doses of anti-Aß immuno-therapies. ARIA is often asymptomatic and self-resolving. The recognition of ARIA has implications for patient selection and monitoring for Aß immunotherapies, and its development can potentially lead to a pause or discontinuation of therapy. The FDA's first approval of an Aß-targeting monoclonal antibody for AD treatment in 2021 will lead to such therapy's expanded use beyond the clinical trial setting and to radiologists more commonly encountering ARIA in clinical practice. This review explores the theorized pathophysiologic mechanisms for ARIA, describes the MRI findings and grading schemes for ARIA-E and AREA-H, and summarizes relevant Aß immunotherapies. Through such knowledge, radiologists can optimally impact the management of patients receiving targeted AD therapies.

The Norton Healthcare electronic antimicrobial stewardship program: An opt-out approach to antimicrobial stewardship.

PURPOSE: To describe the Norton Healthcare electronic antimicrobial stewardship program (E-ASP), a novel prospective audit and feedback approach that leverages the electronic medical record to overcome efficiency barriers. Additionally, to describe an accompanying opt-out antimicrobial stewardship approach that addresses provider nonresponsiveness. SUMMARY: Prospective audit and feedback is recommended by antimicrobial stewardship guidelines; however, execution can be difficult due to labor requirements, delays in communication, and provider nonparticipation. The Norton E-ASP was developed to address these issues by reliably identifying target patients, documenting assessments, streamlining recommendation delivery, promoting handoff, and providing automated tracking of recommendation responses. Opt-out stewardship allows recommendations to be implemented if not rejected after 24 hours. CONCLUSION: A 25% reduction in target antimicrobial use has been achieved and sustained with the program. Use of the Norton E-ASP, including opt-out antimicrobial stewardship, broadened the reach and furthered the impact of infectious diseases pharmacists. Successes of this program justified addition of 3 full-time infectious diseases pharmacist positions at a large community health system. This strategy may serve as a model for tele-antimicrobial stewardship or other pharmacy recommendations.