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.

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.

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.

Deep brain stimulation of the "medial forebrain bundle": sustained efficacy of antidepressant effect over years.

Deep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle (MFB) has emerged as a quite efficacious therapy for treatment resistant depression (TRD), leading to rapid antidepressant effects. In this study, we complete our assessment of our first 10 enrolled patients throughout one year post-implantation, showing sustained antidepressant effect up to 5 years. The primary outcome measure was a 50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score, which was interpreted as a response. Deterministic fiber tracking was used to individually map the target area. An insertional effect was seen during the 4-week sham stimulation phase (29% mean MADRS reduction, p = 0.02). However, after 2 weeks of initiating stimulation, five patients met response criteria (47% mean MADRS reduction, p < 0.001). One patient withdrew from study participation at 6 weeks. Twelve weeks after initiating stimulation, six of nine remaining patients had a >50% decrease in MADRS scores relative to baseline (52% mean MADRS reduction, p = 0.001); these same six patients continued to meet response criteria at 52 weeks (63% overall mean MADRS reduction, p < 0.001). Four of five patients who achieved the 5-year time point analysis continued to be responders (81% mean MADRS reduction, p < 0.001). Evaluation of modulated fiber tracts reveals significant common prefrontal/orbitofrontal connectivity to the target region in all responders. Key points learned from this study that we can incorporate in future protocols to better elucidate the effect of this therapy are a longer blinded sham stimulation phase and use of scheduled discontinuation concomitant with functional imaging.

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.

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.

Neuroinflammation is highest in areas of disease progression in semantic dementia.

Despite epidemiological and genetic data linking semantic dementia to inflammation, the topography of neuroinflammation in semantic dementia, also known as the semantic variant of primary progressive aphasia, remains unclear. The pathology starts at the tip of the left temporal lobe where, in addition to cortical atrophy, a strong signal appears with the tau PET tracer 18F-flortaucipir, even though the disease is not typically associated with tau but with TDP-43 protein aggregates. Here, we characterized the topography of inflammation in semantic variant primary progressive aphasia using high-resolution PET and the tracer 11C-PBR28 as a marker of microglial activation. We also tested the hypothesis that inflammation, by providing non-specific binding targets, could explain the 18F-flortaucipir signal in semantic variant primary progressive aphasia. Eight amyloid-PET-negative patients with semantic variant primary progressive aphasia underwent 11C-PBR28 and 18F-flortaucipir PET. Healthy controls underwent 11C-PBR28 PET (n = 12) or 18F-flortaucipir PET (n = 12). Inflammation in PET with 11C-PBR28 was analysed using Logan graphical analysis with a metabolite-corrected arterial input function. 18F-flortaucipir standardized uptake value ratios were calculated using the cerebellum as the reference region. Since monoamine oxidase B receptors are expressed by astrocytes in affected tissue, selegiline was administered to one patient with semantic variant primary progressive aphasia before repeating 18F-flortaucipir scanning to test whether monoamine oxidase B inhibition blocked flortaucipir binding, which it did not. While 11C-PBR28 uptake was mostly cortical, 18F-flortaucipir uptake was greatest in the white matter. The uptake of both tracers was increased in the left temporal lobe and in the right temporal pole, as well as in regions adjoining the left temporal pole such as insula and orbitofrontal cortex. However, peak uptake of 18F-flortaucipir localized to the left temporal pole, the epicentre of pathology, while the peak of inflammation 11C-PBR28 uptake localized to a more posterior, mid-temporal region and left insula and orbitofrontal cortex, in the periphery of the damage core. Neuroinflammation, greatest in the areas of progression of the pathological process in semantic variant primary progressive aphasia, should be further studied as a possible therapeutic target to slow disease progression.

The impact of the microbiota-gut-brain axis on Alzheimer's disease pathophysiology.

The gut microbiota is a complex ecosystem that comprises of more than 100 trillion symbiotic microbial cells. The microbiota, the gut, and the brain form an association, 'the microbiota-gut-brain axis,' and synchronize the gut with the central nervous system and modify the behavior and brain immune homeostasis. The bidirectional communication between gut and brain occurs via the immune system, the vagus nerve, the enteric nervous system, and microbial metabolites, including short-chain fatty acids (SCFAs), proteins, and tryptophan metabolites. Recent studies have implicated the gut microbiota in many neurodegenerative diseases, including Alzheimer's disease (AD). In this review, we present an overview of gut microbiota, including Firmicutes, Bacteroidetes, SCFA, tryptophan, bacterial composition, besides age-related changes in gut microbiota composition, the microbiota-gut-brain axis pathways, the role of gut metabolites in amyloid-beta clearance, and gut microbiota modulation from experimental and clinical AD models. Understanding the role of the microbiota may provide new targets for treatment to delay the onset, progression, or reverse AD, and may help in reducing the prevalence of AD.

Increased Vascular Pathology in Older Veterans With a Purple Heart Commendation or Chronic Post-Traumatic Stress Disorder.

The goal of this retrospective cohort study was to determine whether stressors related to military service, determined by a diagnosis of chronic post-traumatic stress disorder (cPTSD) or receiving a Purple Heart (PH), are associated with an increased risk of vascular risk factors and disease, which are of great concern for veterans, who constitute a significant portion of the aging US population. The Veterans Integrated Service Network (VISN) 16 administrative database was searched for individuals 65 years or older between October 1, 1997 to September 30, 1999 who either received a PH but did not have cPTSD (PH+/cPTSD-; n = 1499), had cPTSD without a PH (PH-/cPTSD+; n = 3593), had neither (PH-/cPTSD-; n = 5010), or had both (PH+/cPTSD+; n = 153). In comparison to the control group (PH-/cPTSD-), the PH+/cPTSD- group had increased odds ratios for incidence and prevalence of diabetes mellitus, hypertension, and hyperlipidemia. The PH-/cPTSD+ group had increased odds ratios for prevalence of diabetes mellitus and for the incidence and prevalence of hyperlipidemia. The PH-/cPTSD+ and PH+/cPTSD- groups were associated with ischemic heart disease and cerebrovascular disease, but not independently of the other risk factors. The PH+/cPTSD+ group was associated only with an increase in the incidence and prevalence of hyperlipidemia, though this group's much smaller sample size may limit the reliability of this finding. We conclude that certain physical and psychological stressors related to military service are associated with a greater incidence of several vascular risk factors in veterans aged 65 years or older, which in turn are associated with greater rates of ischemic heart disease and cerebrovascular disease.

Sex, race, ADHD, and prior concussions as predictors of concussion recovery in adolescents.

OBJECTIVE: Concussions in adolescents are a growing public health concern as the popularity of high school sports increases. The aim of this study was to identify clinical (e.g., prior concussion, migraine history, learning disabilities/attention deficit hyperactivity disorders [ADHD]) and demographic factors (e.g., sex, race, health insurance, mechanism of injury/sport, education) that predict concussion recovery times. DESIGN: In a retrospective cohort study of adolescents 13-19 years old evaluated for an acute concussion (≤ 10 days from injury), recovery times were calculated from the date of concussive injury to the date of clearance to return to play or normal activities. RESULTS: The sample (N = 227) was primarily male (75%), and the median age was 15 years. Predictors of protracted recovery were ADHD (hazard ratio [HR] =.449, 95% confidence interval [CI] =.272-.741, p = .002) and prior concussion (HR =.574, 95% CI =.397-.828, p = .003) in all sex and race groups, while shorter recovery times were predicted by Hispanic and African American race (HR = 2.12, 95% CI = 1.30-3.46, p = .003), with White females as the reference group. CONCLUSIONS: Further research is needed to examine the role of sex, race, ADHD, and concussion history on concussion outcomes.

Medical-encounter mental health diagnoses, non-fatal injury and polypharmacy indicators of risk for accident death in the US Army enlisted soldiers, 2004-2009.

Accidents are a leading cause of deaths in U.S. active duty personnel. Understanding accident deaths during wartime could facilitate future operational planning and inform risk prevention efforts. This study expands prior research, identifying health risk factors associated with U.S. Army accident deaths during the Afghanistan and Iraq war. Military records for 2004-2009 enlisted, active duty, Regular Army soldiers were analyzed using logistic regression modeling to identify mental health, injury, and polypharmacy (multiple narcotic and/or psychotropic medications) predictors of accident deaths for current, previously, and never deployed groups. Deployed soldiers with anxiety diagnoses showed higher risk for accident deaths. Over half had anxiety diagnoses prior to being deployed, suggesting anticipatory anxiety or symptom recurrence may contribute to high risk. For previously deployed soldiers, traumatic brain injury (TBI) indicated higher risk. Two-thirds of these soldiers had first TBI medical-encounter while non-deployed, but mild, combat-related TBIs may have been undetected during deployments. Post-Traumatic Stress Disorder (PTSD) predicted higher risk for never deployed soldiers, as did polypharmacy which may relate to reasons for deployment ineligibility. Health risk predictors for Army accident deaths are identified and potential practice and policy implications discussed. Further research could test for replicability and expand models to include unobserved factors or modifiable mechanisms related to high risk. PTSD predicted high risk among those never deployed, suggesting importance of identification, treatment, and prevention of non-combat traumatic events. Finally, risk predictors overlapped with those identified for suicides, suggesting effective intervention might reduce both types of deaths.

Do perceptions of their partners' childbearing desires affect young women's pregnancy risk? Further study of ambivalence.

We explore whether young women's perceptions of their sexual partners' childbearing desires contribute to their risk of pregnancy. We used weekly journal data collected from 787 young women to measure their childbearing desires and their perceptions of their partners' childbearing desires. We then conducted hazard modelling to predict pregnancy risk with variables based on interactions between the women's desires and their perceived partners' desires. Models that include perceived partners' desires perform better than one based on women's desires alone. The best model contains three significant predictors: one confirms the importance of pronatal, ambivalent, and indifferent desires for pregnancy risk; one indicates that the perceived partners' antinatal desires reduce women's pregnancy risk; and one suggests that women who both perceive their partners accurately and are in agreement with them have a lower pregnancy risk. The results indicate that perceived partner data can improve prediction and enhance our understanding of pregnancy risk.

Participation in an Intensive Longitudinal Study with Weekly Web Surveys Over 2.5 Years.

BACKGROUND: Technological advances have made it easier for researchers to collect more frequent longitudinal data from survey respondents via personal computers, smartphones, and other mobile devices. Although technology has led to an increase in data-intensive longitudinal studies, little is known about attrition from such studies or the differences between respondents who complete frequently administered surveys in a timely manner, and respondents who do not. OBJECTIVE: We examined respondent characteristics and behaviors associated with continued and on-time participation in a population-based intensive longitudinal study, using weekly web-based survey interviews over an extended period. METHODS: We analyzed data from the Relationship Dynamics and Social Life study, an intensive longitudinal study that collected weekly web-based survey interviews for 2.5 years from 1003 18- and 19-year-olds to investigate factors shaping the dynamics of their sexual behavior, contraceptive use, and pregnancies. RESULTS: Ordinary least squares and logistic regression analyses showed background respondent characteristics measured at baseline were associated with the number of days respondents remained enrolled in the study, the number of interviews they completed, and the odds that they were late completing interviews. In addition, we found that changes in pregnancy-related behaviors reported in the weekly interviews were associated with late completion of interviews. Specifically, after controlling for sociodemographic, personality, contact information, and prior experience variables, we found that weekly reports such as starting to have sex (odds ratio [OR] 1.17, 95% CI 1.03-1.32, P=.01), getting a new partner (OR 1.76, 95% CI 1.53-2.03, P<.001), stopping the use of contraception (OR 1.28, 95% CI 1.10-1.49, P=.001), and having a new pregnancy (OR 5.57, 95% CI 4.26-7.29, P<.001) were significantly associated with late survey completion. However, young women who reported changes in pregnancy-related behaviors also had lower levels of study attrition, and completed more interviews overall, than did their counterparts. CONCLUSIONS: We found that measures of participation in a longitudinal study with weekly web surveys varied not only by respondent characteristics, but also by behaviors measured across the surveys. Our analyses suggest that respondents who experience the behaviors measured by the study may maintain higher participation levels than respondents who do not experience those behaviors.

Trials of antidiabetic drugs in amyotrophic lateral sclerosis: proceed with caution?

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with limited therapeutic options. Clinical trials of several drugs shown to be effective in the superoxide dismutase (SOD1) model of ALS have shown no or negative effects when tested in humans. Here we discuss the role of pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, which failed to show efficacy in a recently published phase II clinical trial of ALS patients. The antioxidant and anti-inflammatory properties of pioglitazone make it an attractive therapeutic candidate for neurodegenerative disorders. However, its antidiabetic and antidyslipidemic effects might be detrimental, as emerging evidence suggests that some features of the metabolic syndrome may be protective in ALS. A number of clinical studies show that dyslipidemia, high body mass index, and possibly diabetes mellitus type 2 are associated with better clinical outcomes in ALS. This is further corroborated by studies on transgenic animal models and immortalized neuronal cell lines. Finally, the intricate interplay between glucose/lipid metabolism and susceptibility to oxidative damage in neurons warrants a judicious approach in further trials of antidiabetic drugs in ALS.

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.

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.

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.

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.

The peaceful mind program: a pilot test of a cognitive-behavioral therapy-based intervention for anxious patients with dementia.

OBJECTIVES: To assess feasibility and to conduct a preliminary evaluation of outcomes following Peaceful Mind, a cognitive-behavioral therapy-based intervention for anxiety in dementia, relative to usual care. DESIGN: Pilot randomized controlled trial including assessments at baseline and 3 and 6 months. SETTING: Houston, TX. PARTICIPANTS: Thirty-two outpatients diagnosed with mild (47%) or moderate (53%) dementia receiving care through outpatient clinics at the Veterans Affairs medical center, Baylor College of Medicine, Harris County Hospital District, and community day centers for dementia, and their collaterals, who spent at least 8 hours a week with them. INTERVENTION: Peaceful Mind included up to 12 weekly in-home sessions (mean: 8.7, SD: 2.27) during the initial 3 months and up to eight brief telephone sessions (mean: 5.4, SD: 3.17) during months 3-6, involving self-monitoring for anxiety, deep breathing, and optional skills (coping self-statements, behavioral activation, and sleep management). Patients learned skills, and collaterals served as coaches. In usual care, patients received diagnostic feedback, and providers were informed of inclusion status. MEASUREMENTS: Neuropsychiatric Inventory-Anxiety subscale, Rating Anxiety in Dementia scale, Penn State Worry Questionnaire-Abbreviated, Geriatric Anxiety Inventory, Geriatric Depression Scale, Quality of Life in Alzheimer disease, Patient Health Questionnaire, and Client Satisfaction Questionnaire. RESULTS: Feasibility was demonstrated with regard to recruitment, attrition, and treatment characteristics. At 3 months, clinicians rated patients receiving Peaceful Mind as less anxious, and patients rated themselves as having higher quality of life; collaterals reported less distress related to loved ones' anxiety. Although significant positive effects were not noted in other outcomes or at 6-month follow-up, the pilot nature of the trial prohibits conclusions about efficacy. CONCLUSIONS: Results support that Peaceful Mind is ready for future comparative clinical trials.

Hippocampal volumes in patients with chronic combat-related posttraumatic stress disorder: a systematic review.

The authors and others have recently demonstrated that veterans with chronic combat-related PTSD (CR-PTSD) have a twofold increased risk of dementia. To understand this increased incidence, they performed a systematic review of the literature on neuroanatomical differences between veterans with chronic CR-PTSD and control subjects (22 included studies). The hippocampus was most commonly and consistently reported to differ between groups, thereby suggesting the hypothesis that PTSD is associated with smaller hippocampi, which increases the risk for dementia. However, an alternate hypothesis is that smaller hippocampal volumes are a preexisting risk factor for PTSD and dementia. Studies are clearly needed to differentiate between these important possibilities.