Introduction:It is important to study apathy in Alzheimer's disease (AD) to better understand its underlying neurobiology and develop effective interventions. In the current study, we sought to examine the relationships between longitudinal apathy and regional tau burden in cognitively impaired older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Methods:Three hundred and nineteen ADNI participants with mild cognitive impairment (MCI) or AD dementia underwent flortaucipir (FTP) tau positron emission tomography (PET) imaging and clinical assessment with the Neuropsychiatric Inventory (NPI) annually. Longitudinal NPI Apathy (NPI-A) scores were examined in relation to baseline tau PET signal in three a priori selected regions implicated in AD and AD-related apathy (supramarginal gyrus, entorhinal cortex [EC] and rostral anterior cingulate cortex [rACC]). Secondary models were adjusted for global cognition (Mini-Mental State Examination score) and cortical amyloid (florbetapir PET). Results:Higher baseline supramarginal gyrus and EC tau burden were each significantly associated with greater NPI-A over time, while rACC tau was associated with higher NPI-A but did not predict its trajectory over time. These results were retained for supramarginal and EC tau after adjusting models for global cognition and cortical amyloid. Discussion:Our findings suggest that baseline in vivo tau burden in parietal and temporal brain regions affected in AD, and less so in a medial frontal region involved in motivational control, is associated with increasing apathy over time in older adults with MCI and AD dementia. Future work studying emergent apathy in relation to not only core AD pathology but also circuit level dysfunction may provide additional insight into the neurobiology of apathy in AD and opportunities for intervention. Highlights:Tau (Flortaucipir PET) in regions implicated in AD was associated with increasing apathy over timeCortical amyloid was also found to be a robust predictor of the trajectory of apathyEvidence of synergy between regional tau and amyloid in overall higher levels of apathy.

Apathy is the most common neuropsychiatric symptom in Alzheimer’s disease (AD), however there are no approved treatments. In the recent Apathy in Dementia Methylphenidate Trial 2 (ADMET 2), methylphenidate treatment resulted in a significant reduction in apathy with a small to medium effect size. Given these results and the clinical heterogeneity of apathetic AD patients, we assessed the heterogeneity of response to methylphenidate in ADMET 2 to identify individuals who may benefit particularly from this treatment. In this multicenter, randomized, placebo-controlled clinical trial of 177 AD patients with clinically significant apathy, participants were randomized to receive methylphenidate or placebo for 6 months. Twenty-one unplanned potential predictors of treatment outcomes were assessed. Predictors were chosen for multivariate modeling based on estimated effect difference, difference of change in the Neuropsychiatric Inventory (NPI)-apathy subscale of two or more at the 6 month visit. Participants were then grouped into 10 subgroups by their index scores, which were constructed based on the predictors with the biggest difference in effect. Of the 21 predictors, six were chosen for multivariate modelling based on having an effect difference of 2 or more in the NPI apathy score. Four of these predictors had a significant interaction with the treatment. Methylphenidate was more effective in participants less likely to have baseline anxiety (-3.1, 95% CI -5.7 - -0.5, p = 0.023) or agitation (-3.6, 95% CI -6.1 - -1.1, p = 0.005) as measured by the NPI, taking a cholinesterase inhibitor (-4.1, 95% CI -6.7 - -1.3, p = 0.004), taking at least one AD medication (-4.0, 95% CI -6.9 - -1.1, p = 0.008), highly educated (-2.1, 95% CI -5.4 – 1.3, p = 0.231), and low functional capacity (-2.6, 95% CI -5.55 – 0.26, p = 0.076) as measured by the Activities of Daily Living scale. Individuals who were less anxious or agitated, more highly educated, on treatment for Alzheimer’s disease, and with low functional capabilities were more likely to benefit from methylphenidate when compared to placebo. Consistent with its potential activating effects, methylphenidate may be particularly beneficial for subgroup of apathetic AD participants with lower baseline anxiety and agitation.

The public health burden of Alzheimer disease (AD) is increasing with the aging of the U.S. population. Neuropsychiatric symptoms (NPS) add greatly to the public health burden and adversely impact patient and caregiver quality of life, and among these agitation is one of the most problematic with high prevalence and persistence. 1 Lanctôt KL Amatniek J Ancoli-Israel S et al. Neuropsychiatric signs and symptoms of Alzheimer's disease: new treatment paradigms. Alzheimers Dement (N Y). 2017; 3: 440-449 Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar ,2 Steinberg M Tschanz JT Corcoran C et al. The persistence of neuropsychiatric symptoms in dementia: the Cache County Study. Int J Geriatr Psychiatry. 2004; 19: 19-26 Crossref PubMed Scopus (131) Google Scholar Nonpharmacologic interventions are recommended as first-line treatment for NPS in AD, but are limited by a delayed onset of effect and lack of efficacy for more severe agitation and aggression. 3 Ijaopo EO Dementia-related agitation: a review of non-pharmacological interventions and analysis of risks and benefits of pharmacotherapy. Transl Psychiatry. 2017; 7: e1240-e1250 Crossref PubMed Scopus (29) Google Scholar There are no U.S. Food and Drug Administration-approved medications to manage agitation in AD; antipsychotics are widely used but have a mixed track record of efficacy and are associated with increased mortality possibly due to cerebrovascular events. Medications being studied include selective serotonin reuptake inhibitors, anticonvulsants, cannabinoids, prazosin, pimavanserin, and dextromethorphan/quinidine among others, but clearly we need to broaden our search for novel treatments in this important area.

ABSTRACT:The COVID-19 pandemic and related measures, such as social distancing, have adversely impacted persons with dementia (PWD) and their caregivers. Nurses must be able to identify the care needs of PWD and their caregivers and intervene with relevant resources.

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.

Abstract Study Objectives To examine in a subsample at the screening phase of a clinical trial of a β-amyloid (Aβ) antibody whether disturbed sleep and altered 24-hour rest/activity rhythms (RARs) may serve as markers of preclinical Alzheimer’s disease (AD). Methods Overall, 26 Aβ-positive (Aβ+) and 33 Aβ-negative (Aβ−) cognitively unimpaired participants (mean age = 71.3 ± 4.6 years, 59% women) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies, respectively, wore actigraphs for 5.66 ± 0.88 24-hour periods. We computed standard sleep parameters, standard RAR metrics (mean estimating statistic of rhythm, amplitude, acrophase, interdaily stability, intradaily variability, relative amplitude), and performed a novel RAR analysis (function-on-scalar regression [FOSR]). Results We were unable to detect any differences between Aβ+ and Aβ− participants in standard sleep parameters or RAR metrics with our sample size. When we used novel FOSR methods, however, Aβ+ participants had lower activity levels than Aβ− participants in the late night through early morning (11:30 pm to 3:00 am), and higher levels in the early morning (4:30 am to 8:30 am) and from midday through late afternoon (12:30 pm to 5:30 pm; all p < .05). Aβ+ participants also had higher variability in activity across days from 9:30 pm to 1:00 am and 4:30 am to 8:30 am, and lower variability from 2:30 am to 3:30 am (all p < .05). Conclusions Although we found no association of preclinical AD with standard actigraphic sleep or RAR metrics, a novel data-driven analytic method identified temporally “local” RAR alterations in preclinical AD.

Although agitation in Alzheimer’s Disease (Agit-AD) is a common and troubling neuropsychiatric syndrome, behavioral interventions lack consistent efficacy and there are no FDA-approved medications. Neurobiological mechanisms that contribute to Agit-AD include brain atrophy, degradation of neurotransmission, neuroinflammation, disrupted circadian rhythms, comorbidities and frailty. Agit-AD is a major source of disease progression, patient disability, financial burden, and caregiver stress. Dronabinol is synthetic tetrahydrocannabinol (THC, one of the predominant biochemical constituents of cannabis). Cannabinoids may improve Agit-AD by providing protection against neuroinflammation and excitotoxicity, regulating neurotransmitters, improving comorbidities, stabilizing circadian rhythms, and increasing cerebral blood flow. THC-AD is a three-week placebo-controlled, double-blind, RCT of dronabinol (10 mg QD) in 80 patients with severe Agit-AD. Twice daily administration maximizes daytime coverage for agitation and minimizes sundowning. Inclusionary criteria include a diagnosis of AD, severe agitation, and being 60-95 years old, while exclusionary criteria include serious or unstable medical illness, seizure disorder, delirium, current use of lithium, and inability to swallow a pill. Primary outcomes include a change in the Pittsburgh Agitation Scale and NPI-C Agitation/Aggression subscales. We have enrolled 37 out of 80 participants (Table 1: mean age 78.2 years, 78.4% female, 83.8% Caucasian, mean education 13.2 years, 48.6% family history). Study participants are significantly cognitively impaired (Table 2: mean baseline MMSE of 7.1), agitated (mean NPI-C Agitation 14.8, mean NPI-C Aggression 6.4) and in reasonable overall health (Figure 1: General Medical Health Rating, 10.8% “excellent,” 48.6% "good" and 40.5% "fair”). Recorded AEs have been tolerable (Figure 2). Due to the COVID-19 pandemic, we expanded our inpatient trial to include outpatient enrollments and implemented hybrid visits with telemedicine to limit in-person interactions. To bolster our recruitment, we are collaborating with additional clinical sites, increasing dementia bed capacity, and deploying recruitment strategies for outpatients, including referrals from providers and other research trials, social media ads, and virtual community outreach. Updated results will be presented at AAIC (estimated 6-10 additional participants). Safe and effective interventions for severe agitation are greatly needed. This pilot trial will help to examine the safety and efficacy of dronabinol for Agit-AD.

Apathy is among the earliest and most clinically distressing neuropsychiatric symptoms (NPS) in Alzheimer’s Disease (AD). Examining the relationships between apathy and AD pathology is needed to better understand neurobiological mechanisms for therapeutic intervention that could delay disease progression. Research has shown that tau may correlate more closely with cognitive and behavioral manifestations in AD than amyloid. In the current study, we examined the relationship between regional tau burden and longitudinal change in apathy in older adults with mild cognitive impairment (MCI) and AD dementia from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. A total of 319 ADNI participants (233 with MCI; 86 with AD dementia; age: 75.5 ±8.2; 56% female) underwent flortaucipir (FTP) tau positron emission tomography (PET) and clinical assessment with the Neuropsychiatric Inventory (NPI) every 6-12 months (average follow up= 39.1 months). The NPI Apathy (NPI-A) score was examined in relation to tau PET signal in four FreeSurfer defined regions of interest implicated in AD and mood regulation: entorhinal cortex (EC), precuneus, inferior temporal cortex and rostral anterior cingulate cortex (rACC). Separate linear mixed models examined the association between NPI-A (for each study visit) and FTP SUVR in the above regions and their interactions with time as predictors of interest. Age and sex were included as covariates. Higher precuneus, EC and inferior temporal cortex tau were each significantly associated with greater NPI-A over time (precuneus: ß=0.0273; t=5.01; 95 % CI (0.016, 0.04); p<0.001; EC: ß=0.023; t=5.05; 95 % CI (0.014, 0.032); p<0.001; inferior temporal: ß=.018; t=4.92; 95 % CI (0.011, 0.026); p<0.001. rACC tau was marginally associated with higher NPI-A over time: ß=.013; t=1.93; 95 % CI (-0.00, 0.027) p=0.05. These findings suggest that tau burden in brain regions associated with AD, and less so with mood regulation, is associated with increasing apathy over time in individuals with MCI and AD dementia. Further study of emergent apathy in relation to core AD pathology and other neurobiological mechanisms will provide insight into opportunities for interventions that could slow clinical progression and alleviate patient and caregiver burden.

Agitation is a common complication of Alzheimer's dementia (Agit-AD) associated with substantial morbidity, high healthcare service utilization, and adverse emotional and physical impact on care partners. There are currently no FDA-approved pharmacological treatments for Agit-AD. We present the study design and baseline data for an ongoing multisite, three-week, double-blind, placebo-controlled, randomized clinical trial of dronabinol (synthetic tetrahydrocannabinol [THC]), titrated to a dose of 10 mg daily, in 80 participants to examine the safety and efficacy of dronabinol as an adjunctive treatment for Agit-AD. Preliminary findings for 44 participants enrolled thus far show a predominately female, white sample with advanced cognitive impairment (Mini Mental Status Examination mean 7.8) and agitation (Neuropsychiatric Inventory-Clinician Agitation subscale mean 14.1). Adjustments to study design in light of the COVID-19 pandemic are described. Findings from this study will provide guidance for the clinical utility of dronabinol for Agit-AD. ClinicalTrials.gov Identifier: NCT02792257.

Dementia is characterized by a significant decline in one of several cognitive domains such as memory, language and executive function, affecting independence and representing a significant deterioration from a previous level of functioning (1). Alzheimer’s Disease (AD) represents the most common form of dementia and contributes up to 70% of the almost 50 million dementia cases worldwide, a number that is projected to double in 20 years (2).

Background To present methodology, baseline results and longitudinal course of the Agitation and Aggression in patients with Alzheimer’s Disease Cohort (A3C) study. Objectives The central objective of A3C was to study the course, over 12 months of clinically significant Agitation and Aggression symptoms based on validated measures, and to assess relationships between symptoms and clinical significance based on global ratings. Design A3C is a longitudinal, prospective, multicenter observational cohort study performed at eight memory clinics in France, and their associated long-term care facilities. Setting Clinical visits were scheduled at baseline, monthly during the first 3 months, at 6 months, at 9 months and at 12 months. The first three months intended to simulate a classic randomized control trial 12-week treatment design. Participants Alzheimer’s Disease patients with clinically significant Agitation and Aggression symptoms lived at home or in long-term care facilities. Measurements Clinically significant Agitation and Aggression symptoms were rated on Neuropsychiatric Inventory (NPI), NPI-Clinician rating (NPI-C) Agitation and Aggression domains, and Cohen Mansfield Agitation Inventory. Global rating of agitation over time was based on the modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change. International Psychogeriatric Association “Provisional Diagnostic Criteria for Agitation”, socio-demographics, non-pharmacological approaches, psychotropic medication use, resource utilization, quality of life, cognitive and physical status were assessed. Results A3C enrolled 262 AD patients with a mean age of 82.4 years (SD ±7.2 years), 58.4% women, 69.9% at home. At baseline, mean MMSE score was 10.0 (SD±8.0), Cohen Mansfield Agitation Inventory score was 62.0 (SD±15.8) and NPI-C Agitation and Aggression clinician severity score was 15.8 (SD±10.8). According to the International Psychogeriatric Association agitation definition, more than 70% of participants showed excessive motor activity (n=199, 76.3%) and/or a verbal aggression (n=199, 76.3%) while 115 (44.1%) displayed physical aggression. The change of the CMAI score and the NPI-C Agitation and Aggression at 1-year follow-up period was respectively −11.36 (Standard Error (SE)=1.32; p<0.001) and −6.72 (SE=0.77; p<0.001). Conclusion Little is known about the longitudinal course of clinically significant agitation symptoms in Alzheimer’s Disease about the variability in different outcome measures over time, or the definition of a clinically meaningful improvement. A3C may provide useful data to optimize future clinical trials and guide treatment development for Agitation and Aggression in Alzheimer’s Disease.

The public health burden of Alzheimer's disease (AD) is related not only to cognitive symptoms, but also to neuropsychiatric symptoms, including apathy. Apathy is defined as a quantitative reduction of goal-directed activity in comparison to a previous level of functioning and affects 30%-70% of persons with AD. Previous attempts to treat apathy in AD-both nonpharmacologically and pharmacologically-have been wanting. Catecholaminergic treatment with methylphenidate has shown encouraging results in initial trials of apathy in AD. Understanding the neuronal circuits underlying motivated behavior and their reliance on catecholamine actions helps provide a rationale for methylphenidate actions in the treatment of apathy in patients with AD. Anatomical, physiological, and behavioral studies have identified parallel, cortical-basal ganglia circuits that govern action, cognition, and emotion and play key roles in motivated behavior. Understanding the distinct contributions to motivated behavior of subregions of the prefrontal cortex-dorsolateral, orbital-ventromedial, and dorsomedial-helps to explain why degeneration of these areas in AD results in apathetic behaviors. We propose that the degeneration of the prefrontal cortex in AD produces symptoms of apathy. We further propose that methylphenidate treatment may ameliorate those symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits.

BACKGROUND/OBJECTIVES There are growing concerns about the safety and efficacy of psychotropic medications in Alzheimer's disease (AD). We sought to examine associations between psychotropic medication exposure and longitudinal change in cognitive, functional, and neuropsychiatric outcomes in a large clinical AD cohort. DESIGN Longitudinal observational study. SETTING National Alzheimer's Disease Coordinating Center combining data from 39 Alzheimer's disease centers. PARTICIPANTS 8,034 participants with AD dementia. MEASUREMENTS Mini‐Mental State Exam (MMSE), Clinical Dementia Rating Scale‐Sum of Boxes (CDR‐SB), and Neuropsychiatric Inventory Questionnaire (NPI‐Q) Total. Probability of exposure to medication (the propensity score, PS) calculated via logistic regression. Medication classes included all antipsychotics (atypical vs conventional), antidepressants (Selective Serotonin Reuptake Inhibitor [SSRI] vs non‐SSRI), and benzodiazepines. Participants treated with a medication class were matched with participants not treated with that class with the closest‐matched PS. The effect of medication treatment was assessed using linear mixed‐effects models. RESULTS Participants had a mean (SD) age of 75.5 (9.8) years, and mean (SD) scores of MMSE 21.3 (5.7), CDR‐SB 5.5 (3.4), and NPI‐Q Total 4.5 (4.4). Mean duration of follow‐up was 2.9–3.3 years depending on medication class. Non‐SSRI antidepressant use was associated with better CDR‐SB (2‐year difference in change‐DIC: −0.38 [−0.61, −0.15], P = .001). Atypical antipsychotic use was associated with greater decline on MMSE (DIC: −0.91 [−1.54, −0.28] P = .005) and CDR‐SB scores (DIC: 0.50 [0.14, 0.86], P = .006). Notably, no drug class was associated with better NPI‐Q scores. CONCLUSIONS Use of atypical antipsychotics was associated with poorer cognition and function, and no drug class was associated with improvement in neuropsychiatric symptoms.

Jennifer R. Gatchel, MD, PhD; Jennifer S. Rabin, PhD; Rachel F. Buckley, PhD; Joseph J. Locascio, PhD; Yakeel T. Quiroz, PhD; Hyun-Sik Yang, MD; Patrizia Vannini, PhD; Rebecca E. Amariglio, PhD; Dorene M. Rentz, PsyD; Michael Properzi, BEng; Nancy J. Donovan, MD; Deborah Blacker, MD, ScD; Keith A. Johnson, MD; Reisa A. Sperling, MD; Gad A. Marshall, MD; for the Harvard Aging Brain Study

Neuropsychiatric symptoms (NPS) add greatly to the public health burden of Alzheimer's disease (AD) and adversely impact patient and caregiver quality of life. Agitation is one of the most prominent NPS in AD with high prevalence and persistence. Nonpharmacologic interventions are recommended as first-line treatment for NPS in AD, but are limited by a delayed onset of effect and lack of efficacy for more severe agitation and aggression. Although medications are widely used to treat NPS in AD, none are U.S. Food and Drug Administration (FDA) approved and one widely used class of medications (antipsychotics) is associated with increased mortality and risk of cerebrovascular adverse effects (AEs). More effective and better tolerated medications for NPS in AD are sorely needed.

11C-RO-963, 11C-RO-643, and 18F-RO-948 (previously referred to as 11C-RO6924963, 11C-RO6931643, and 18F-RO6958948, respectively) have been reported as promising PET tracers for tau imaging based on in vitro and preclinical PET data. Here we describe the first, to our knowledge, human evaluation of these novel radiotracers. Methods: Amyloid PET–positive Alzheimer disease (AD) subjects and younger controls each received 2 different tau tracers. Dynamic 90-min scans were obtained after bolus injection of 11C-RO-963, 11C-RO-643, or 18F-RO-948. Arterial blood sampling was performed on 11 healthy controls and 11 AD subjects. Regions were defined on MR images, and PET data were quantified by plasma reference graphical analysis (for total distribution volume) and target cerebellum ratio (SUV ratios of 60- to 90-min frames). SUV ratio images were also analyzed voxelwise. Five older controls each underwent 2 scans with 18F-RO-948 for evaluation of test–retest variability. Four AD subjects underwent a repeated 18F-RO-948 scan 6–22 mo after the first scan. Six additional healthy controls (3 men and 3 women; age range, 41–67 y) each underwent 1 whole-body dosimetry scan with 18F-RO-948. Results: In younger controls, SUVpeak was observed in the temporal lobe with values of approximately 3.0 for 11C-RO-963, 1.5 for 11C-RO-643, and 3.5 for 18F-RO-948. Over all brain regions and subjects, the trend was for 18F-RO-948 to have the highest SUVpeak, followed by 11C-RO-963 and then 11C-RO-643. Regional analysis of SUV ratio and total distribution volume for 11C-RO-643 and 18F-RO-948 clearly discriminated the AD group from the healthy control groups. Compartmental modeling confirmed that 11C-RO-643 had lower brain entry than either 11C-RO-963 or 18F-RO-948 and that 18F-RO-948 showed better contrast between (predicted) areas of high versus low tau accumulation. Thus, our subsequent analysis focused on 18F-RO-948. Both voxelwise and region-based analysis of 18F-RO-948 binding in healthy controls versus AD subjects revealed multiple areas where AD subjects significantly differed from healthy controls. Of 22 high-binding regions, 13 showed a significant group difference (after ANOVA, F(1,21) = 45, P < 10−5). Voxelwise analysis also revealed a set of symmetric clusters where AD subjects had higher binding than healthy controls (threshold of P < 0.001, cluster size > 50). Conclusion:18F-RO-948 demonstrates characteristics superior to 11C-RO-643 and 11C-RO-963 for characterization of tau pathology in AD. Regional binding data and kinetic properties of 18F-RO-948 compare favorably with other existing tau PET tracers.

BACKGROUND:Deaths from drug intoxication have increased in the United States but outcomes of recipients of orthotopic heart transplantation (OHT) from these donors are not well characterized. METHODS:We performed a retrospective analysis of the United Network for Organ Sharing's STAR database between January 2000 and March 2014 and assessed mortality and retransplantation using adjusted Cox models by mechanism of donor death. RESULTS:Of the 31,660 OHTs from 2000 to 2014, 1233 (3.9%) were from drug intoxication. These donors were more likely to be female, white, with greater tobacco use and higher BMI compared to donors who died of other mechanisms. Drug intoxication accounted for 1.1% of OHT donors in 2000 and 6.2% in March 2014. No significant difference was observed in 10-year mortality (adjusted hazard ratio [HR], 95% confidence interval [CI]: 0.99, 0.87-1.13), 10-year retransplantation (adjusted HR 0.84, 0.49-1.41) or 1-year and 3-year rehospitalization with other mechanisms of death compared to drug intoxication. CONCLUSION:There has been a large increase in OHT donors who die of drug intoxication in the United States. OHT outcomes from these donors are similar to those dying from other mechanisms. These data have important implications for donor selection in context of the ongoing opioid epidemic.

ABSTRACTObjective:There is increasing evidence of an association between depressive symptoms and mild cognitive impairment (MCI) in cross-sectional studies, but the longitudinal association between depressive symptoms and risk of MCI onset is less clear. The authors investigated whether baseline symptom severity of depression was predictive of time to onset of symptoms of MCI.Method:These analyses included 300 participants from the BIOCARD study, a cohort of individuals who were cognitively normal at baseline (mean age = 57.4 years) and followed for up to 20 years (mean follow-up = 2.5 years). Depression symptom severity was measured using the Hamilton Depression Scale (HAM-D). The authors assessed the association between dichotomous and continuous HAM-D and time to onset of MCI within 7 years versus after 7 years from baseline (reflecting the mean time from baseline to onset of clinical symptoms in the cohort) using Cox regression models adjusted for gender, age, and education.Results:At baseline, subjects had a mean HAM-D score of 2.2 (SD = 2.8). Higher baseline HAM-D scores were associated with an increased risk of progression from normal cognition to clinical symptom onset ≤ 7 years from baseline (p= 0.043), but not with progression > 7 years from baseline (p= 0.194). These findings remained significant after adjustment for baseline cognition.Conclusions:These results suggest that low levels of depressive symptoms may be predictive of clinical symptom onset within approximately 7 years among cognitively normal individuals and may be useful in identifying persons at risk for MCI due to Alzheimer’s disease.