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There is a limited understanding of the cognitive and psychiatric sequelae of COVID-19 during the post-acute phase, particularly among racially and ethnically diverse patients.We sought to prospectively characterize cognition, mental health symptoms, and functioning approximately four months after an initial diagnosis of COVID-19 in a racially and ethnically diverse group of patients.Approximately four months after COVID-19 diagnosis, patients in the Johns Hopkins Post-Acute COVID-19 Team Pulmonary Clinic underwent a clinical telephone-based assessment of cognition, depression, anxiety, trauma, and function.Most Johns Hopkins Post-Acute COVID-19 Team patients assessed were women (59%) and members of racial/ethnic minority groups (65%). Of 82 patients, 67% demonstrated ≥1 abnormally low cognitive score. Patients requiring intensive care unit (ICU) stays displayed greater breadth and severity of impairment than those requiring less intensive treatment. Processing speed (35%), verbal fluency (26%-32%), learning (27%), and memory (27%) were most commonly impaired. Among all patients, 35% had moderate symptoms of depression (23%), anxiety (15%), or functional decline (15%); 25% of ICU patients reported trauma-related distress. Neuropsychiatric symptoms and functional decline did not differ by post-ICU versus non-ICU status and were unrelated to global cognitive composite scores.At approximately 4 months after acute illness, cognitive dysfunction, emotional distress, and functional decline were common among a diverse clinical sample of COVID-19 survivors varying in acute illness severity. Patients requiring ICU stays demonstrated greater breadth and severity of cognitive impairment than those requiring less intensive treatment. Findings help extend our understanding of the nature, severity, and potential duration of neuropsychiatric morbidity after COVID-19 and point to the need for longitudinal assessment of cognitive and mental health outcomes among COVID-19 survivors of different demographic backgrounds and illness characteristics.

Minority older adults face multiple barriers when trying to access mental health services and often present with more severe symptoms of mental health conditions. We describe the multilevel factors that contributed to the engagement of an Asian immigrant older adult with depression. Systems-level innovations such as collaborative care in primary care can increase access to care for all, including minority older adults; however, one size fits all interventions may not meet the needs of communities of older adults with different life experiences, language needs, norms and values regarding help-seeking for mental health. Health outcomes remain unequal , suggesting the need to tailor interventions for minority older adults. For the patient, specific factors related to language and ethnic concordance between patient and healthcare provider, communication behaviors, ethnic identity, and social norms may be important to take into account. The recognition of the heterogeneity of patients and the limitations of cultural competence approaches defined as broad, general knowledge about ethnic cultures may be needed. A need to learn continuously from clinical experience and adopt a patient-oriented model of communication and decision-making may successfully engage Asian immigrant older adults in depression care services.

Objectives While there is growing evidence of an association between depressive symptoms and postoperative delirium, the underlying pathophysiological mechanisms remain unknown. The goal of this study was to explore the association between depression and postoperative delirium in hip fracture patients, and to examine Alzheimer's disease (AD) pathology as a potential underlying mechanism linking depressive symptoms and delirium. Methods Patients 65 years old or older (N = 199) who were undergoing hip fracture repair and enrolled in the study “A Strategy to Reduce the Incidence of Postoperative Delirium in Elderly Patients” completed the 15-item Geriatric Depression Scale (GDS-15) preoperatively. Cerebrospinal fluid (CSF) was obtained during spinal anesthesia and assayed for amyloid-beta (Aβ) 40, 42, total tau (t-tau), and phosphorylated tau (p-tau)181. Results For every one point increase in GDS-15, there was a 13% increase in odds of postoperative delirium, adjusted for baseline cognition (MMSE), age, sex, race, education and CSF AD biomarkers (OR = 1.13, 95%CI = 1.02–1.25). Both CSF Aβ42/t-tau (β = −1.52, 95%CI = −2.1 to −0.05) and Aβ42/p-tau181 (β = −0.29, 95%CI = −0.48 to −0.09) were inversely associated with higher GDS-15 scores, where lower ratios indicate greater AD pathology. In an analysis to identify the strongest predictors of delirium out of 18 variables, GDS-15 had the highest classification accuracy for postoperative delirium and was a stronger predictor of delirium than both cognition and AD biomarkers. Conclusions In older adults undergoing hip fracture repair, depressive symptoms were associated with underlying AD pathology and postoperative delirium. Mild baseline depressive symptoms were the strongest predictor of postoperative delirium, and may represent a dementia prodrome.

Neuropsychiatric symptoms (NPS) in persons with dementia (PWD) are common and can lead to poor outcomes, such as institutionalization and mortality, and may be exacerbated by sensory loss. Hearing loss is also highly prevalent among older adults, including PWD. Objective This study investigated the association between hearing loss and NPS among community- dwelling patients from a tertiary memory care center. Design, Setting, and Participants Participants of this cross-sectional study were patients followed at the Johns Hopkins Memory and Alzheimer's Treatment Center who underwent audiometric testing during routine clinical practice between October 2014 and January 2017. Outcome Measurements Included measures were scores on the Neuropsychiatric Inventory–Questionnaire and the Cornell Scale for Depression in Dementia. Results Participants (n = 101) were on average 76 years old, mostly female and white, and had a mean Mini-Mental State Examination score of 23. We observed a positive association between audiometric hearing loss and the number of NPS (b = 0.7 per 10 dB; 95% confidence interval [CI]: 0.2, 1.1; t = 2.86; p = 0.01; df = 85), NPS severity (b = 1.3 per 10 dB; 95% CI: 0.4, 2.5; t = 2.13; p = 0.04; df = 80), and depressive symptom severity (b = 1.5 per 10 dB; 95% CI: 0.4, 2.5; t = 2.83; p = 0.01; df = 89) after adjustment for demographic and clinical characteristics. Additionally, the use of hearing aids was inversely associated with the number of NPS (b = −2.09; 95% CI −3.44, −0.75; t = −3.10; p = 0.003; df = 85), NPS severity (b = −3.82; 95% CI −7.19, −0.45; t = −2.26; p = 0.03; df = 80), and depressive symptom severity (b = −2.94; 95% CI: −5.93, 0.06; t = 1.70; p = 0.05; df = 89). Conclusion Among patients at a memory clinic, increasing severity of hearing loss was associated with a greater number of NPS, more severe NPS, and more severe depressive symptoms, while hearing aid use was associated with fewer NPS, lower severity, and less severe depressive symptoms. Identifying and addressing hearing loss may be a promising, low-risk, non-pharmacological intervention in preventing and treating NPS.

Introduction There has been considerable progress in identifying early cognitive and biomarker predictors of Alzheimer's disease (AD). Neuropsychiatric symptoms (NPS) are common in AD and appear to predict progression after the onset of mild cognitive impairment or dementia. Objectives The objective of the study is to examine the relationship between NPS in clinically normal older adults and subsequent cognitive decline in a population-based sample. Methods The Cache County Study on Memory in Aging consists of a population-based sample of 5,092 older adults. We identified 470 clinically normal adults who were followed for an average period of 5.73 years. NPS were evaluated at the baseline clinical assessment using the Neuropsychiatric Inventory (NPI). NPI domain scores were quantified as the product of frequency X severity in individual NPI domains, and then summed for the NPI-Total. Neuropsychological measures were collected at baseline and at each subsequent follow-up wave. Linear mixed-effects models assessed the association of NPI-Total, NPI-Depression, and NPI-Anxiety scores (obtained at baseline) on longitudinal change in neuropsychological performance, controlling for age, sex, and education. Results Baseline NPI-Total score was associated with a more rapid rate of decline in word list memory, praxis recall, and animal fluency. Baseline NPI-Depression was not associated with later decline on any of the cognitive tests, while baseline NPI-Anxiety was associated with decline in Symbol Digit Modality. Conclusion In conclusion, among clinically normal older adults derived from this population-based study, total burden of NPS was associated with longitudinal cognitive decline. These results add to the evidence that NPS are risk factors for or clinical indicators of preclinical dementia syndrome. Our study was an exploratory study and we did not control for multiple comparisons.

Antipsychotic reductions have been the primary focus of efforts to improve dementia care in nursing homes by the Centers for Medicare & Medicaid Services National Partnership. Although significant antipsychotic reductions have been achieved, this policy focus is myopic in 2 ways; there is no evidence for any increases in use of nonpharmacologic interventions, and there are indications for compensatory increases in the use of other (unmeasured) sedating psychotropics. This increased use of other sedating psychotropics is more concerning than the antipsychotics that they replaced, as there is even less support of efficacy for behavioral and psychological symptoms of dementia (BPSD) and ample proof of harms, including mortality. The current paradigm of "assessment" and "treatment" for BPSD is largely cursory and reflexive, with little effort put forth to understand possible underlying causes. This contrasts with the methodical, evidence-based way the field handles other symptoms considered "medical" (eg, shortness of breath). To move beyond this nonmedical approach to BPSD, we suggest a conceptual model that includes putative causal contributors. Although at their core BPSD are caused by brain circuitry disruptions, such disruptions are theorized to increase the person with dementia's vulnerability to 3 categories of triggers: those related to the (1) patient (eg, pain, hunger, and infection), (2) caregivers (eg, competing priorities, unrealistic expectations, and negative communications), and (3) environment (eg, overstimulation and limited light exposure). Assessing modifiable triggers is inherently person-centered as it enables clinicians to select specific nonpharmacologic strategies to mitigate identified triggers. Assessing triggers and selecting strategies, however, is time-intensive and reflects a paradigm shift necessitating a reorganization of dementia care including compensation for time spent elucidating and addressing modifiable triggers, vs unintendedly incentivizing the use of potentially harmful psychotropics. This paradigm shift should also include the measurement and restriction of any sedating medications for BPSD, particularly without assessment of underlying causes.

Objective Closer caregiver-care recipient (CG-CR) relationships are associated with better cognitive and functional abilities, activities of daily living (in persons with dementia), and lower informal care costs. Methods Due to the difficulty in treating neuropsychiatric symptoms (NPSs) and their detrimental effects on caregivers and care recipients, we examined whether closeness of CG-CR relationships was associated with overall NPS severity or with specific NPS symptom domains in care recipients. In a longitudinal population-based study in Cache County, Utah, the 12-item Neuropsychiatric Inventory (NPI-12) was assessed in 300 CG-CR dyads. Caregivers reported current relationship closeness using the Whitlatch Relationship Closeness Scale. Linear mixed models examined associations between CG-CR closeness and NPI-12 total score or selected symptom domains over time (observation period: 2002–2012). Results In unadjusted linear mixed models, higher closeness scores were associated with a five-point lower NPI-12 score and a one-point lesser increase in NPI-12 per year. NPI scores also showed lower affective cluster scores (two points) and lesser increase in psychosis cluster (approximately 0.5 points per year) and agitation/aggression (0.16 points per year) for each unit increase in closeness. When controlling for NPI caregiver distress, associations between closeness and NPSs diminished to a 0.5-point lesser increase in total NPI-12 score per year. Adjusted models for NPI domains/clusters showed −0.32 points per year for the psychosis cluster, −0.11 points per year for agitation/aggression, and −0.67 overall for the affective cluster. Conclusion Higher CG-CR closeness, a potentially modifiable factor, is associated with lower NPS severity and may provide a target for intervention.

Background Dementia is associated with high health care costs, premature long-term care (LTC) placement, medical complications, reduced quality of life, and caregiver burden. Most health care providers and systems are not yet organized or equipped to provide comprehensive long-term care management for dementia, although a range of effective symptoms and supportive care approaches exist. The Maximizing Independence at Home-Streamlined (MIND-S) is a promising model of home-based dementia care coordination designed to efficiently improve person-centered outcomes, while reducing care costs. This report describes the rationale and design of an NIA-funded randomized controlled trial to test the impact of MIND-S on time to LTC placement, person with dementia outcomes (unmet needs, behavior, quality of life), family caregiver outcomes (unmet needs, burden), and cost offset at 18 (primary end point) and 24 months, compared to an augmented usual care group. Methods This is a 24-month, parallel group, randomized trial evaluating MIND-S in a cohort of 304 community-living persons with dementia and their family caregivers in Maryland. MIND-S dyads receive 18 months of care coordination by an interdisciplinary team comprised of trained non-clinical community workers (e.g. Memory Care Coordinators), a registered nurse, and a geriatric psychiatrist. Intervention components include in-home dementia-related needs assessments; individualized care planning; implementation of standardized evidence-based care strategy protocols; and ongoing monitoring and reassessment. Outcomes are assessed by blinded evaluators at baseline, 4.5, 9, 13.5, 18, and 24 months. Discussion Trial results will provide rigorous data to inform innovations in effective system-level approaches to dementia care.

Dementia-related behavioral symptoms are challenging clinical features occurring across etiologies and disease progression. They are associated with increased healthcare utilization, nursing home placement, family upset and burden. Families typically manage behavioral symptoms without requisite knowledge, skills and guidance. We designed WeCareAdvisor™ as an easy-to-use, evidence-informed web-based platform. It provides families knowledge about dementia, daily tips, and a systematic approach to describe behaviors, investigate modifiable contributors, create treatment plans (WeCareAdvisor™ Prescription) consisting of management tips tailored to symptom presentation, and evaluate effectiveness. WeCareAdvisor™ is being tested in a randomized trial to assess acceptability, usability and immediate impact on caregiver confidence managing and upset with behavioral symptoms, and secondarily, frequency of behavioral occurrences. Fifty-seven caregivers will be enrolled from communities and medical clinics at two sites (University of Michigan; Johns Hopkins University). Families reporting behavioral symptoms in a telephone screen are consented and interviewed at home. Following the interview, an envelope is opened by interviewers to reveal group assignment (immediate vs one-month delayed treatment group). Those receiving WeCareAdvisor™ immediately are provided an iPad and instruction in its use; those in the delayed treatment group are informed of next study steps. All caregivers are reassessed at home one month from baseline. The delayed treatment group then receives iPad instructions and are re-interviewed one month thereafter. During treatment phase, participants receive 3 weekly check-in calls to encourage tool use and troubleshoot. Key outcomes include number of times using WeCareAdvisor™ and for which behaviors, self-efficacy and upset managing behavioral symptoms, and frequency of behavioral occurrences. Clinical trial registration #: NCT02420535.

AIMS: We examined whether problem-solving and diabetes self-management behaviors differ by depression diagnosis - major depressive disorder (MDD) and minor depressive disorder (MinDD) - in adults with Type 2 diabetes (T2DM). METHODS: We screened a clinical sample of 702 adults with T2DM for depression, identified 52 positive and a sample of 51 negative individuals, and performed a structured diagnostic psychiatric interview. MDD (n = 24), MinDD (n = 17), and no depression (n = 62) were diagnosed using Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) Text Revised criteria. Health Problem-Solving Scale (HPSS) and Summary of Diabetes Self-Care Activities (SDSCA) questionnaires determined problem-solving and T2DM self-management skills, respectively. We compared HPSS and SDSCA scores by depression diagnosis, adjusting for age, sex, race, and diabetes duration, using linear regression. RESULTS: Total HPSS scores for MDD (β = −4.38; p < 0.001) and MinDD (β = −2.77; p < 0.01) were lower than no depression. Total SDSCA score for MDD (β = −10.1; p < 0.01) was lower than for no depression, and was partially explained by total HPSS. CONCLUSION: MinDD and MDD individuals with T2DM have impaired problem-solving ability. MDD individuals had impaired diabetes self-management, partially explained by impaired problem-solving. Future studies should assess problem-solving therapy to treat T2DM and MinDD and integrated problem-solving with diabetes self-management for those with T2DM and MDD.

Chronic vulvar pain is alarmingly common in women of reproductive age and is often accompanied by psychological distress, sexual dysfunction, and a significant reduction in quality of life. Localized provoked vulvodynia (LPV) is associated with intense vulvar pain concentrated in the vulvar vestibule (area surrounding vaginal opening). To date, the origins of vulvodynia are poorly understood, and treatment for LPV manages pain symptoms, but does not resolve the root causes of disease. Until recently, no definitive disease mechanisms had been identified; our work indicates LPV has inflammatory origins, although additional studies are needed to understand LPV pain. Bradykinin signaling is one of the most potent inducers of inflammatory pain and is a candidate contributor to LPV. We report that bradykinin receptors are expressed at elevated levels in LPV patient versus healthy control vestibular fibroblasts, and patient vestibular fibroblasts produce elevated levels of proinflammatory mediators with bradykinin stimulation. Inhibiting expression of one or both bradykinin receptors significantly reduces proinflammatory mediator production. Finally, we determined that bradykinin activates nuclear factor (NF)κB signaling (a major inflammatory pathway), whereas inhibition of NFκB successfully ablates this response. These data suggest that therapeutic agents targeting bradykinin sensing and/or NFκB may represent new, more specific options for LPV therapy. Perspective There is an unmet need for the development of more effective vulvodynia therapies. As we explore the mechanisms by which human vulvar fibroblasts respond to proinflammatory/propain stimuli, we move closer to understanding the origins of chronic vulvar pain and identifying new therapeutic targets, knowledge that could significantly improve patient care.

Among over 5million people in the USA with dementia, neuropsychiatric symptoms (NPS) are almost universal, occurring across disease etiology and stage. If untreated, NPS can lead to significant morbidity and mortality including increased cost, distress, depression, and faster disease progression, as well as heightened burden on families. With few pharmacological solutions, identifying nonpharmacologic strategies is critical. We describe a randomized clinical trial, the Dementia Behavior Study, to test the efficacy of an activity program to reduce significant existing NPS and associated caregiver burden at 3 and 6months compared to a control group intervention. Occupational therapists deliver 8 in-home sessions over 3months to assess capabilities and interests of persons with dementia, home environments, and caregiver knowledge, and readiness from which activities are developed and families trained in their use. Families learn to modify activities for future declines and use strategies to address care challenges. The comparison group controls for time and attention and involves 8 in-home sessions delivered by health educators who provide dementia education, home safety recommendations, and advanced care planning. We are randomizing 250 racially diverse families (person with dementia and primary caregiver dyads) recruited from community-based social services, conferences and media announcements. The primary outcome is change in agitation/aggression at 3 and 6months. Secondary outcomes assess quality of life of persons with dementia, other behaviors, burden and confidence of caregivers, and cost and cost effectiveness. If benefits are supported, this activity intervention will provide a clinically meaningful approach to prevent, reduce, and manage NPS.

Background We found a benefit of citalopram for agitation in the Citalopram for Agitation in Alzheimer's Disease study (CitAD), and wondered if this was mediated by a sedative effect. CitAD was a randomized, placebo-controlled, double-blind, parallel group trial conducted at 8 academic centers in the United States and Canada from August 2009 to January 2013. One hundred sixty-two participants with probable Alzheimer's disease (AD) and clinically significant agitation were analyzed in this study. Participants received a psychosocial intervention and were randomized to receive either citalopram or placebo (approximately half assigned to each group). Participants were rated on the Neurobehavioral Rating Scale Agitation subscale and measures of sedation (i.e., fatigue and somnolence). Methods Using the MacArthur Foundation procedures for documenting a mediator effect, we performed a secondary analysis examining whether sedation mediates the effect of treatment on agitation outcome. Results: We found a statistically significant mediating effect of sedation on agitation outcomes, but the magnitude of the effect was small, only explaining 11% of the variance in agitation, with a significant, but modest effect size of 0.16 (95% CI: 0.08 to 0.22). Conclusions The benefit of citalopram was partly due to sedation but largely due to other mechanisms of action.

Introduction Plasma levels of amyloid‐beta (Aβ) do not correlate well with different stages of Alzheimer's disease (AD) in cross‐sectional studies. Measuring the changes in Aβ plasma levels with an acute intervention may be more sensitive to distinguishing individuals in earlier stages of AD (mild cognitive impairment [MCI]) from normal controls. Methods A total of 57 participants (18 with AD/MCI and 39 cognitively normal controls) underwent oral glucose tolerance testing (OGTT). Blood samples were obtained over a 2‐hour period. Changes in plasma Aβ40 and 42 levels were measured from either baseline or 5 minutes to the 10‐minute time‐point. Results Compared with normal controls, subjects with AD/MCI had significantly less change (Δ) in plasma levels for both Aβ40 (−3.13 [40.93] vs. 41.34 pg/mL [57.16]; P = .002) and Aβ42 (−0.15 [3.77] vs. 5.64 pg/mL [10.65]; P = .004). Discussion OGTT combined with measures of plasma Aβ40 and 42 is potentially useful in distinguishing aging individuals who are in different stages of AD.

Objective To provide a critical review of a multipronged recruitment approach used to identify, recruit, and enroll a diverse community-based sample of persons with memory disorders into an 18-month randomized, controlled dementia care coordination trial. Methods Descriptive analysis of a recruitment approach comprised five strategies: community liaison ("gatekeepers") method, letters sent from trusted community organizations, display and distribution of study materials in the community, research registries, and general community outreach and engagement activities. Participants were 55 community organizations and 63 staff of community organizations in Baltimore, Maryland. Participant referral sources, eligibility, enrollment status, demographics, and loss to follow-up were tracked in a relational access database. Results In total, 1,275 referrals were received and 303 socioeconomically, cognitively, and racially diverse community-dwelling persons with cognitive disorders were enrolled. Most referrals came from letters sent from community organizations directly to clients on the study's behalf (39%) and referrals from community liaison organizations (29%). African American/black enrollees were most likely to come from community liaison organizations. Conclusion A multipronged, adaptive approach led to the successful recruitment of diverse community-residing elders with memory impairment for an intervention trial. Key factors for success included using a range of evidence-supported outreach strategies, forming key strategic community partnerships, seeking regular stakeholder input through all research phases, and obtaining "buy-in" from community stakeholders by aligning study objectives with perceived unmet community needs.

The number of people living with dementia worldwide is estimated at 44 million, with projections indicating this number will double by 2030 and more than triple by 2050 (1). Neuropsychiatric symptoms (NPS) accompany cognitive decline almost universally, with 98% of patients experiencing NPS at some point in their illness (2). NPS are especially concerning as they are associated with more rapid disease progression, worse patient outcomes, excess morbidity and mortality, greater healthcare utilization, earlier nursing home placement, and increased caregiver burden (3, 4). Treatment of NPS may alter disease course, improve patient outcomes, decrease healthcare costs, and improve patient and caregiver quality of life.

There are growing concerns about potential delayed, neuropsychiatric consequences (e.g, cognitive decline, mood or anxiety disorders) of sports-related traumatic brain injury (TBI). Autopsy studies of brains from a limited number of former athletes have described characteristic, pathologic changes of chronic traumatic encephalopathy (CTE) leading to questions about the relationship between these pathologic and the neuropsychiatric disturbances seen in former athletes. Research in this area will depend on in vivo methods that characterize molecular changes in the brain, linking CTE and other sports-related pathologies with delayed emergence of neuropsychiatric symptoms. In this pilot project we studied former National Football League (NFL) players using new neuroimaging techniques and clinical measures of cognitive functioning. We hypothesized that former NFL players would show molecular and structural changes in medial temporal and parietal lobe structures as well as specific cognitive deficits, namely those of verbal learning and memory. We observed a significant increase in binding of [(11)C]DPA-713 to the translocator protein (TSPO), a marker of brain injury and repair, in several brain regions, such as the supramarginal gyrus and right amygdala, in 9 former NFL players compared to 9 age-matched, healthy controls. We also observed significant atrophy of the right hippocampus. Finally, we report that these same former players had varied performance on a test of verbal learning and memory, suggesting that these molecular and pathologic changes may play a role in cognitive decline. These results suggest that localized brain injury and repair, indicated by increased [(11)C]DPA-713 binding to TSPO, may be linked to history of NFL play. [(11)C]DPA-713 PET is a promising new tool that can be used in future study design to examine further the relationship between TSPO expression in brain injury and repair, selective regional brain atrophy, and the potential link to deficits in verbal learning and memory after NFL play.

Objective We wanted to assess if sertraline treatment (versus placebo) or remission of depression at 12 weeks (versus nonremission) in Alzheimer patients is associated with improved caregiver well being. Methods We conducted a randomized, double-blind, placebo-controlled clinical trial of the efficacy and safety of sertraline for the treatment of depression in individuals with Alzheimer disease in five clinical research sites across the United States. Participants were caregivers of patients enrolled in the Depression in Alzheimer's Disease Study 2 (N = 131). All caregivers received standardized psychosocial support throughout the study. Caregiver outcome measures included depression (Beck Depression Inventory), distress (Neuropsychiatric Inventory), burden (Zarit Burden Interview), and quality of life (Medical Outcomes Study Short Form Health Survey). Results Fifty-nine percent of caregivers were spouses, 63.4% were women, and 64.1% were white. Caregivers of patients in both treatment groups had significant reductions in distress scores over the 24-week study period, but there was not a greater benefit for caregivers of patients taking sertraline. However, caregivers of patients whose depression was in remission at week 12 had greater declines in distress scores over the 24 weeks than caregivers of patients whose depression did not remit by week 12. Conclusion Patient treatment with sertraline was not associated with significantly greater reductions in caregiver distress than placebo treatment. Distress but not level of depression or burden lessened for all caregivers regardless of remission status and even more so for those who cared for patients whose depression remitted. Results imply an interrelationship between caregiver distress and patient psychiatric outcomes.

Objectives To examine the association of neuropsychiatric symptom (NPS) severity with risk of transition to all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD). Design Survival analysis of time to dementia, AD, or VaD onset. Setting Population-based study. Participants 230 participants diagnosed with cognitive impairment, no dementia (CIND) from the Cache County Study of Memory Health and Aging were followed for a mean of 3.3 years. Measurements The Neuropsychiatric Inventory (NPI) was used to quantify the presence, frequency, and severity of NPS. Chi-squared statistics, t -tests, and Cox proportional hazard ratios were used to assess associations. Results The conversion rate from CIND to all-cause dementia was 12% per year, with risk factors including an APOE e4 allele, lower Mini-Mental State Examination, lower 3MS, and higher CDR sum-of-boxes. The presence of at least one NPS was a risk factor for all-cause dementia, as was the presence of NPS with mild severity. Nighttime behaviors were a risk factor for all-cause dementia and of AD, whereas hallucinations were a risk factor for VaD. Conclusions These data confirm that NPS are risk factors for conversion from CIND to dementia. Of special interest is that even NPS of mild severity are a risk for all-cause dementia or AD.

Ribonucleoside phosphonate analogues containing 2'-α-fluoro modifications were synthesized and their potency evaluated against HCV RNA polymerase. The diphosphophosphonate (triphosphate equivalent) adenine and cytidine analogues displayed potent inhibition of the HCV polymerase in the range of 1.9-2.1 μM, but only modest cell-based activity in the HCV replicon. Pro-drugs of the parent nucleoside phosphonates improved the cell-based activity.

Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)–based tests ( P −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE e4 allele with NFIC SNP. We also obtained GWS evidence ( P −6 ) for gene-based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

Landmark studies have established taxanes in the treatment of patients with breast cancer; however, recommendations regarding their administration during pregnancy are controversial. The present systematic review aims to synthesize all available data that stem exclusively from breast cancer case series to evaluate the efficacy and safety of taxanes during pregnancy. Overall, 16 studies (50 pregnancies) were eligible for the systematic review according to prisma guidelines. The mean age of patients with breast cancer at pregnancy was 34.6 years. The gestational age (GA) at chemotherapy administration varied from 12 to 36 weeks. The mean GA at delivery was 35.9 weeks. The mean weight of babies at delivery was 2380 g. In 76.7% of cases, a completely healthy neonate was born; in the remaining cases, a neonate who was dystrophic and premature, one with mild hydrocephalus, one with signs of bacterial sepsis, one with hyperbilirubinemia, one with apnea of prematurity, respiratory distress syndrome and gastroesophageal reflux, one with meconium-stained fluid, and another neonate with neutropenia and pyloric stenosis were reported. Ninety percent of children were completely healthy, with a median follow-up of 16 months; in the remaining cases, one child with recurrent otitis media, one with immunoglobulin A deficiency and mild constipation, and another child with delayed speech were reported. In conclusion, available data suggest that taxanes may potentially play a promising role in the optimal therapeutic strategy of patients with breast cancer diagnosed during pregnancy.

Objective To review systematically, for the first time, the effectiveness of all pharmacologic interventions to improve quality of life and well-being in people with dementia. Design Systematic review and meta-analysis. Methods We systematically reviewed the 15 randomized controlled trials and one review that fitted predetermined criteria. We included studies that reported the outcomes quality of life, well-being, happiness, or pleasure. Measurements We rated the validity of studies using a checklist. We calculated mean differences between intervention and control groups at follow-up. Results None of the evaluated trials reported a significant benefit to quality of life or well-being for people with dementia when comparing those taking a drug or its comparator at follow-up (pooled weighted mean difference: 0.18 [95% confidence interval: −0.82 to 0.46]). Conclusion We found no consistent evidence that any drug improves quality of life in people with dementia. We recommend that all dementia trials should include quality of life as an outcome, as this is important to patients, and cannot be presumed from improvements in cognition or other symptomatic outcomes, especially if the latter are small.

Objectives Few longitudinal studies have studied the influence of the care environment on the clinical progression of dementia. We examined whether caregiver coping strategies predict dementia progression in a population-based sample. Design Longitudinal, prospective cohort study. Setting Cache County (Utah) population. Participants A total of 226 persons with dementia, and their caregivers, were assessed semiannually for up to 6 years. Measurements Ways of Coping Checklist–Revised, Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR). Results Mean (SD) age of dementia onset in persons with dementia was 82.11 (5.84) years and mean caregiver age was 67.41 (13.95) years. Mean (SD) follow-up was 1.65 (1.63) years from baseline. In univariate linear mixed-effects models, increasing use of problem-focused and counting blessings by caregivers was associated with slower patient worsening on the MMSE. Problem-focused coping, seeking social support, and wishful thinking were associated with slower Clinical Dementia Rating Scale sum of boxes (CDR-sb) worsening. Considering covariates, increasing use of problem-focused coping was associated with 0.70 points per year less worsening on the MMSE and 0.55 points per year less worsening on the CDR-sb. Compared with no use, the "regular" use of this strategy was associated with 2 points per year slower worsening on the MMSE and 1.65 points per year slower worsening on the CDR-sb. Conclusions Caregiver coping strategies are associated with slower dementia progression. Developing interventions that target these strategies may benefit dementia patients.

Objective Practice effects on cognitive tests have been shown to further characterize patients with amnestic mild cognitive impairment (aMCI) and may provide predictive information about cognitive change across time. We tested the hypothesis that a loss of practice effects would portend a worse prognosis in aMCI. Design Longitudinal, observational design following participants across 1 year. Setting Community-based cohort. Participants Three groups of older adults: 1) cognitively intact (n = 57), 2) aMCI with large practice effects across 1 week (MCI + PE, n=25), and 3) aMCI with minimal practice effects across 1 week (MCI − PE, n=26). Measurements Neuropsychological tests. Results After controlling for age and baseline cognitive differences, the MCI − PE group performed significantly worse than the other groups after 1 year on measures of immediate memory, delayed memory, language, and overall cognition. Conclusions Although these results need to be replicated in larger samples, the loss of short-term practice effects portends a worse prognosis in patients with aMCI.

T proposed changes to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-4) category, currently labeled dementia, delirium, amnestic, and other cognitive disorders, attempts to address issues of phenomenology, severity, comorbidity, and etiology while also producing a scheme that is usable for researchers, clinicians, teachers, and administrators. In this commentary we respond to the recent draft revision of the fourth edition of the DSM-4 developed by the American Psychiatric Association. Our intent is to provide constructive recommendations to be considered in the next iteration as we move toward the DSM-5. The major guiding principle that we apply is that changes in the classification scheme should incorporate advances in knowledge and represent the conditions and patients that it is intended to differentiate. Cognitive disorders affect one or more cognitive faculties (e.g., memory alone, language alone, several combinations), present in mild or severe form (such as day-to-day functioning is unaffected, minimally affected, or clearly affected), and are associated with a range of other psychiatric symptoms (such as depression, delusions, agitation). To further complicate matters, impaired cognition can be a consequence of a wide range of injuries and situations including genetic abnormalities, toxins, metabolic derangerments, neurodegenerative disorders (e.g., Alzheimer disease), stroke, traumatic brain injury, or primary

Background Depression and antidepressant use are common in Alzheimer disease (AD), but the effect of antidepressant treatment for depression on longer term outcomes is unknown. The authors report the Week-24 outcomes of patients who participated in a 12-week efficacy study of sertraline for depression of AD. Methods One hundred thirty-one participants (sertraline = 67, placebo=64) with mild-moderate AD and depression participated in the study. Patients who showed improvement on the modified Alzheimer's Disease Cooperative Study Clinical Global Impression-Change (mADCS-CGIC) after 12 weeks of randomized treatment with sertraline or placebo continued double-blinded treatment for an additional 12 weeks. Depression response and remission at 24 weeks were based on mADCS-CGIC score and change in Cornell Scale for Depression in Dementia (CSDD) score. Secondary outcome measures included time to remission, nonmood neuropsychiatric symptoms, global cognition, function, and quality of life. Results One hundred seventeen (89.3%) participants completed all study assessments and 74 (56.5%; sertraline=38, placebo=36) completed all 24 weeks on randomized treatment. By 24 weeks, there were no between-group differences in depression response (sertraline = 44.8%, placebo=35.9%; odds ratio [95% CI] = 1.23 [0.64–2.35]), change in CSDD score (median difference=0.6 [95% CI: −2.26 to 3.46], χ 2 [ df = 2] = 1.03), remission rates (sertraline = 32.8%, placebo=21.8%; odds ratio [95% CI] = 1.61 [0.70–3.68]), or secondary outcomes. Common selective serotonin reuptake inhibitor-associated adverse events, specifically diarrhea, dizziness, and dry mouth, and pulmonary serious adverse events were more frequent in sertraline-randomized patients than in placebo subjects. Conclusions Sertraline treatment is not associated with delayed improvement between 12 and 24 weeks of treatment and may not be indicated for the treatment of depression of AD.

GS-9148 ([5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl]-phosphonic acid) is a dAMP (2'-deoxyadenosine monophosphate) analog that maintains its antiviral activity against drug-resistant HIV. Crystal structures for HIV-1 reverse transcriptase (RT) bound to double-stranded DNA, ternary complexes with either GS-9148-diphosphate or 2'-deoxyadenosine triphosphate (dATP), and a post-incorporation structure with GS-9148 translocated to the priming site were obtained to gain insight into the mechanism of RT inhibition. The binding of either GS-9148-diphosphate or dATP to the binary RT-DNA complex resulted in the fingers subdomain closing around the incoming substrate. This produced up to a 9 A shift in the tips of the fingers subdomain as it closed toward the palm and thumb subdomains. GS-9148-diphosphate shows a similar binding mode as dATP in the nucleotide-binding site. Residues whose mutations confer resistance to nucleotide/nucleoside RT inhibitors, such as M184, Y115, L74, and K65, show little to no shift in orientation whether GS-9148-diphosphate or dATP is bound. One difference observed in binding is the position of the central ring. The dihydrofuran ring of GS-9148-diphosphate interacts with the aromatic side chain of Y115 more than does the ribose ring of dATP, possibly picking up a favorable pi-pi interaction. The ability of GS-9148-diphosphate to mimic the active-site contacts of dATP may explain its effective inhibition of RT and maintained activity against resistance mutations. Interestingly, the 2'-fluoro moiety of GS-9148-diphosphate was found in close proximity to the Q151 side chain, potentially explaining the observed moderately reduced susceptibly to GS-9148 conferred by Q151M mutation.

Objective Depression is common in Alzheimer disease (AD), and antidepressants are commonly used for its treatment, however, evidence for antidepressant efficacy in this population is lacking. The authors conducted a multicenter, randomized, placebo-controlled trial titled "Depression in Alzheimer's Disease-2" to assess the efficacy and tolerability of sertraline for depression in AD. Methods One hundred thirty-one participants from five U.S. medical centers with mild-to-moderate AD (Mini-Mental State Examination scores 10-26) and depression of AD were randomized to double-blinded treatment with sertraline (N = 67) or placebo (N = 64), with a target dosage of 100 mg daily. Efficacy was assessed using logistic regressions and mixed effects models in an intention-to-treat analysis with imputation of missing data. Principal outcome measures were modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC), change in Cornell Scale for Depression in Dementia (CSDD) scores, and remission defined by both mADCS-CGIC score ≤2 and CSDD score ≤6. Results mADCS-CGIC ratings (odd ratio [OR = 1.01], 95% confidence interval [CI]: 0.52-1.97, p=0.98), CSDD scores (median difference at 12 weeks 1.2, 95% CI: 1.65-4.05, p=0.41), and remission at 12 weeks of follow-up (OR = 2.06, 95% CI: 0.84-5.04, p=0.11) did not differ between sertraline (N = 67) and placebo (N = 64). Sertraline-treated patients experienced more adverse events, most notably gastrointestinal and respiratory, than placebo-treated patients. Conclusion Sertraline did not demonstrate efficacy for the treatment depression symptoms in patients with AD. In addition, its use was associated with an increased incidence of adverse events. Thus, selective serotonin reuptake inhibitors may be of limited value for treating depression in patients with AD.

To describe and contrast functional dependency (FD) levels among recently admitted AL residents with and without dementia and to assess the differential contribution of cognitive, behavioral, medical, and social factors on FD within each group.A cross-sectional study.A random sample of 28 AL facilities in the Central Maryland region.Two hundred and sixty-two AL residents assessed less than 1 year after admission.Participants were given comprehensive in-person dementia assessments. Cognitive, behavioral, medical, and social factors were also assessed. FD was operationalized as impairment in activities of daily living.The 59% of residents with dementia had higher levels of FD (P.001) and were more likely to require assistance in all assessed task-specific ADL domains (P.001) except mobility (P = .653). In multivariate models, global cognition, medical health status, and presence of diabetes explained 43% of the variance in FD in the dementia group. Twenty-five percent of the variance in FD was explained by depression, neuropsychiatric symptoms, and global cognition in those without dementia.Recently admitted AL residents have substantial levels of FD. FD is higher among residents with dementia compared with those without and the association of cognitive, mental health, and medical variables with FD differ as a function of dementia status. Future research should examine how these dimensions affect FD longitudinally and whether they may serve as targets for interventions and quality of care improvement initiatives.

A diphosphate of a novel cyclopentyl based nucleoside phosphonate with potent inhibition of HIV reverse transcriptase (RT) (20, IC(50)=0.13 microM) has been discovered. In cell culture the parent phosphonate diacid 9 demonstrated antiviral activity EC(50)=16 microM, within two-fold of GS-9148, a prodrug of which is currently under clinical investigation, and within 5-fold of tenofovir (PMPA). In vitro cellular metabolism studies using 9 confirmed that the active diphosphate metabolite is produced albeit at a lower efficiency relative to GS-9148.

Background Although increasing numbers of older adults are living in assisted living facilities, there is little information on the types and amount of chronic medical illness and the medications required by such residents. To better inform efforts to optimize care in this setting, we sought to quantify chronic medical illnesses and their treatment. Methods Medical diagnoses and treatments were derived from chart reviews and interviews of 198 residents of 22 randomly selected assisted living facilities (AL) in central Maryland. To evaluate the burden of medical illnesses, chronic conditions were categorized and quantified according to general (organ system) diseases, as well as 7 specific long-term care Clinical Practice Guidelines (CPG). Using logistic regression, we calculated the associations between facility-level characteristics and those residents with a) conditions from 3 or more general disease categories and, b) 2 or more CPG conditions. To evaluate medical treatment complexity, we categorized oral and certain non-oral medications, as well medications that typically require additional monitoring. Results Almost one-half (46%) of AL residents had chronic conditions in 3 or more different general disease categories and one-fourth (25.2%) had 2 or more specific Clinical Practice Guideline (CPG) conditions. Residents with chronic conditions in 3 or more different general disease groups were more likely to live in larger facilities; otherwise, no other facility-level characteristics that we assessed were associated with residents having conditions from 3 or more general disease categories or 2 or more CPG conditions. One-half of all residents were taking medications that typically require additional monitoring and 25% of residents were receiving treatments of respiratory inhalers, eye drops and/or injections. Conclusions Many AL residents have multiple medical illnesses of different types and complexity. Given the increasing role of AL providers in the management of such conditions, appropriate adjustments in care provision will be needed for facilities to meet the needs of these residents.

GS-9148 (2'-Fd4AP, 4) has been identified as a nucleoside phosphonate reverse transcriptase (RT) inhibitor with activity against wild-type HIV (EC(50)=12 microM). Unlike many clinical RT inhibitors, relevant reverse transcriptase mutants (M184V, K65R, 6-TAMs) maintain a susceptibility to 2'-Fd4AP that is similar to wild-type virus. The 2'-fluorine group was rationally designed into the molecule to improve the selectivity profile and in preliminary studies using HepG2 cells, compound 4 showed no measurable effect on mitochondrial DNA content indicating a low potential for mitochondrial toxicity.