Search

Over 40 million people worldwide suffer from dementia. This number is projected to exceed 110 million by 2050 because of the aging of the worldwide population, especially in lower- and middle-income countries. The most common cause of dementia is believed to be Alzheimer's, a brain disease associated with deposition of beta-amyloid protein and hyperphosphorylation of intraneuronal tau protein leading to synaptic degradation, neuronal loss, brain circuit disruption, a range of symptoms, and eventually, if the person lives long enough, death. Over the last few decades, treatment development has focused on the deposition of beta-amyloid protein (A-beta 1-42) that is produced in the brain in huge quantities continuously and is thought to be toxic. Unfortunately, amyloid oriented therapies targeting individuals with dementia, or its prodrome mild cognitive impairment (MCI), have not been successful therapeutically even though they have been associated with reductions in amyloid. Currently, efforts are underway to deliver these therapies to individuals with very early symptoms or at risk for Alzheimer's dementia by virtue of genetics or a brain amyloid PET scan. Results from these studies are expected to begin to emerge by early 2020. In the meantime, since the amyloid hypothesis has been called into question, a number of different avenues are being pursued for treatment development. These are driven in part by new findings related to the polygenic nature of Alzheimer's as well as the interaction between this brain disease with factors such as brain vascular disease, insulin resistance, and/or brain inflammation. The expected future of AD treatment development is thought to be precision medicine.

Objectives: To identify subtypes of neuropsychiatric symptom (NPS) course among cognitively normal individuals and to assess the association between these subtypes and hazard of later mild cognitive impairment (MCI) or dementia diagnosis., Methods: We modeled neuropsychiatric inventory questionnaire (NPI-Q) scores from 4184 volunteers over approximately 4 years using growth mixture models, generating latent classes of trajectory. We then fit Cox proportional hazard models to determine if membership in trajectory classes was associated with increased hazard of diagnosis of MCI or dementia., Results: We identified four trajectory classes: the majority of the sample (65%) would be expected to belong to a class with consistently low or zero NPS. The next most prevalent class, (16%) showed a decrease over time in NPI-Q total score but, compared with the majority class had an almost threefold increase in hazard of MCI or dementia (HR: 2.92; 95% CI: 1.82-4.68). Another class (14%) showed an increase in NPS over time and was also associated with greater hazard of MCI or dementia (HR: 3.96; CI: 2.61-6.03). The smallest class (5%) had high and fluctuating NPI-Q total scores and had the greatest hazard (HR: 4.57; CI: 2.72-7.63)., Conclusion: We have demonstrated that it is possible to identify meaningful groups of NPS trajectories and that trajectory of NPS can convey information beyond a single cross-sectional measure. While even those whose NPS improved were at increased hazard of MCI or dementia, hazard increased as a function of the severity of the NPS trajectory., (© 2019 John Wiley & Sons, Ltd.)

Importance: Blood biomarkers able to diagnose Alzheimer disease (AD) at the preclinical stage would enable trial enrollment when the disease is potentially reversible. Plasma neuronal-enriched extracellular vesicles (nEVs) of patients with AD were reported to exhibit elevated levels of phosphorylated (p) tau, Aβ42, and phosphorylated insulin receptor substrate 1 (IRS-1)., Objective: To validate nEV biomarkers as AD predictors., Design, Setting, Participants: This case-control study included longitudinal plasma samples from cognitively normal participants in the Baltimore Longitudinal Study of Aging (BLSA) cohort who developed AD up to January 2015 and age- and sex-matched controls who remained cognitively normal over a similar length of follow-up. Repeated samples were blindly analyzed over 1 year from participants with clinical AD and controls from the Johns Hopkins Alzheimer Disease Research Center (JHADRC). Data were collected from September 2016 to January 2018. Analyses were conducted in March 2019., Main Outcomes and Measures: Neuronal-enriched extracellular vesicles were immunoprecipitated; tau, Aβ42, and IRS-1 biomarkers were quantified by immunoassays; and nEV concentration and diameter were determined by nanoparticle tracking analysis. Levels and longitudinal trajectories of nEV biomarkers between participants with future AD and control participants were compared., Results: Overall, 887 longitudinal plasma samples from 128 BLSA participants who eventually developed AD and 222 age and sex-matched controls who remained cognitively normal were analyzed. Participants were followed up (from earliest sample to AD symptom onset) for a mean (SD) of 3.5 (2.31) years (range, 0-9.73 years). Overall, 161 participants were included in the training set, and 80 were in the test set. Participants in the BLSA cohort with future AD (mean [SD] age, 79.09 [7.02] years; 68 women [53.13%]) had longitudinally higher p-tau181, p-tau231, pSer312-IRS-1, pY-IRS-1, and nEV diameter than controls (mean [SD] age, 76.2 [7.36] years; 110 women [50.45%]) but had similar Aβ42, total tau, TSG101, and nEV concentration. In the training BLSA set, a model combining preclinical longitudinal data achieved 89.6% area under curve (AUC), 81.8% sensitivity, and 85.8% specificity for predicting AD. The model was validated in the test BLSA set (80% AUC, 55.6% sensitivity, 88.7% specificity). Preclinical levels of nEV biomarkers were associated with cognitive performance. In addition, 128 repeated samples over 1 year from 64 JHADRC participants with clinical AD and controls were analyzed. In the JHADRC cohort (35 participants with AD: mean [SD] age, 74.03 [8.73] years; 18 women [51.43%] and 29 controls: mean [SD] age, 72.14 [7.86] years; 23 women [79.31%]), nEV biomarkers achieved discrimination with 98.9% AUC, 100% sensitivity, and 94.7% specificity in the training set and 76.7% AUC, 91.7% sensitivity, and 60% specificity in the test set., Conclusions and Relevance: We validated nEV biomarker candidates and further demonstrated that their preclinical longitudinal trajectories can predict AD diagnosis. These findings motivate further development of nEV biomarkers toward a clinical blood test for AD.

Introduction: Alzheimer's disease (AD) is a disabling, common cause of dementia, and agitation is one of the most common and distressing symptoms for patients with AD. Escitalopram for agitation in Alzheimer's disease (S-CitAD) tests a novel, clinically derived therapeutic approach to treat agitation in patients with AD., Methods: S-CitAD is a NIH-funded, investigator-initiated, randomized, multicenter clinical trial. Participants receive a structured psychosocial intervention (PSI) as standard of care. Participants without sufficient response to PSI are randomized to receive 15 mg escitalopram/day or a matching placebo in addition to PSI. Primary outcome is the Modified Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (mADCS-CGIC)., Discussion: S-CitAD will provide information about a practical, immediately available approach to treating agitation in patients with AD. S-CitAD may become a model of how to evaluate and predict treatment response in patients with AD and agitation as a neuropsychiatric symptom (ClinicalTrials.gov Identifier: NCT03108846)., (Copyright © 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

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., (Published by Elsevier Inc.)

Introduction: The reasons why women are at higher risk than men for developing dementia are unclear. Although studies implicate sex differences in the effect of stress on cognitive functioning, whether stressful life events are associated with subsequent cognitive decline has received scant research attention., Methods: In Wave 3 (1993-1996) of the Baltimore Epidemiologic Catchment Area study, 337 men and 572 women (mean age = 47 years) reported recent (within the last year) and remote (from 1981 until 1 year ago) traumatic events (eg, combat) and stressful life events (eg, divorce/separation). At Waves 3 and 4 (2004-2005), they completed the Mini Mental State Examination (MMSE) and a word-list memory test. Multivariable models were used to examine the association between traumatic and stressful life events at Wave 3 and cognitive change by Wave 4., Results: A greater number of recent stressful life events at Wave 3, but not of more remote stressful events, was associated with greater verbal memory decline by Wave 4 in women but not in men. Stressful events were not associated with change in MMSE, and there were no associations between traumatic events occurring at any time and subsequent memory or MMSE decline in either sex., Conclusions: Unlike men, middle-aged women with a greater number of recent stressful life events demonstrate memory decline over a decade later. Sex differences in cognitive vulnerability to stressful life events may underlie women's increased risk of memory impairment in late life, suggesting that stress reduction interventions may help prevent cognitive decline in women., (© 2019 John Wiley & Sons, Ltd.)

Introduction: Neuropsychiatric symptoms (NPSs) are nearly universal in cognitive disorders. The mild behavioral impairment construct postulates that NPS may be the first symptom of impending dementia., Methods: Participants were cognitively normal volunteers followed up approximately annually at Alzheimer's Disease Centers, who were assessed on the Neuropsychiatric Inventory and had at least one follow-up visit during which they were diagnosed with mild cognitive impairment (MCI) or dementia. Descriptive statistics were used to determine sequencing of NPS presence with cognitive diagnoses., Results: Data were available for 1998 participants who progressed to MCI or dementia. Over 59% developed NPS before the diagnosis of any cognitive disorder. Depression and irritability were the most common NPSs to precede cognitive diagnoses (24 and 21%, respectively)., Discussion: NPSs precede a cognitive diagnosis in most people who develop cognitive decline, both MCI and dementia. These individuals are an important group to focus clinical and research efforts.

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., (Copyright © 2018 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: Severity of dementia and neuropsychiatric symptoms contribute to increasing informal care costs. We examined which neuropsychiatric symptoms subdomains (NPS-SD) were associated with informal costs in a population-based sample., Methods: Dementia progression and informal costs (2015 dollars) were estimated from the Cache County Dementia Progression Study. Overall NPS and specific NPS-SD were assessed with the Neuropsychiatric Inventory. Generalized Estimating Equations (GEE with gamma-distribution/log-link) modeled the relationship between NPS-SDs and informal cost trajectories., Results: Two hundred eighty participants (52.1% female; age M = 85.67, SD = 5.60) exhibited an adjusted cost increase of 5.6% ( P  = .005), 6.4% ( P  < .001), 7.6% ( P  = .030), and 13% ( P  = .024) for every increasing Neuropsychiatric Inventory unit in psychosis-SD, affective-SD, agitation/aggression-SD, and apathy-SD, respectively. An increase in each unit of apathy was associated with a 2% annual decrease in costs ( P  = .040)., Discussion: We extend our prior work on informal costs and dementia severity by identifying NPS-SD associated with informal costs. Interventions targeting NPS-SD may lower informal costs.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10 -7 ), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

For patients with cognitive disorders and dementia, accurate prognosis of cognitive worsening is critical to their ability to prepare for the future, in collaboration with health-care providers. Despite multiple efforts to apply computational brain magnetic resonance image (MRI) analysis in predicting cognitive worsening, with several successes, brain MRI is not routinely quantified in clinical settings to guide prognosis and clinical decision-making. To encourage the clinical use of a cutting-edge image segmentation method, we developed a prediction model as part of an established web-based cloud platform, MRICloud. The model was built in a training dataset from Alzheimer's Disease Neuroimaging Initiative (ADNI) where baseline MRI scans were combined with clinical data over time. Each MRI was parcellated into 265 anatomical units based on the MRICloud fully automated image segmentation function, to measure the volume of each parcel. The Mini Mental State Examination (MMSE) was used as a measure of cognitive function. The normalized volume of 265 parcels, combined with baseline MMSE score, age, and sex were input variables for a Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis, with MMSE change in the subsequent two years as the target for prediction. A leave-one-out analysis performed on the training dataset estimated a correlation coefficient of 0.64 between true and predicted MMSE change. A receiver operating characteristic (ROC) analysis estimated a sensitivity of 0.88 and a specificity of 0.76 in predicting substantial cognitive worsening after two years, defined as MMSE decline of ≥4 points. This MRICloud prediction model was then applied to a test dataset of clinically acquired MRIs from the Johns Hopkins Memory and Alzheimer's Treatment Center (MATC), a clinical care setting. In the latter setting, the model had both sensitivity and specificity of 1.0 in predicting substantial cognitive worsening. While the MRICloud prediction model demonstrated promise as a platform on which computational MRI findings can easily be extended to clinical use, further study with a larger number of patients is needed for validation.

Purpose: To examine the feasibility and potential difficulties of automatically generating radiologic reports (RRs) to articulate the clinically important features of brain magnetic resonance (MR) images. Materials and Methods: We focused on examining brain atrophy by using magnetization-prepared rapid gradient-echo (MPRAGE) images. The technology was based on multi-atlas whole-brain segmentation that identified 283 structures, from which larger superstructures were created to represent the anatomic units most frequently used in RRs. Through two layers of data-reduction filters, based on anatomic and clinical knowledge, raw images (~10 MB) were converted to a few kilobytes of human-readable sentences. The tool was applied to images from 92 patients with memory problems, and the results were compared to RRs independently produced by three experienced radiologists. The mechanisms of disagreement were investigated to understand where machine-human interface succeeded or failed. Results: The automatically generated sentences had low sensitivity (mean: 24.5%) and precision (mean: 24.9%) values; these were significantly lower than the inter-rater sensitivity (mean: 32.7%) and precision (mean: 32.2%) of the radiologists. The causes of disagreement were divided into six error categories: mismatch of anatomic definitions (7.2 ± 9.3%), data-reduction errors (11.4 ± 3.9%), translator errors (3.1 ± 3.1%), difference in the spatial extent of used anatomic terms (8.3 ± 6.7%), segmentation quality (9.8 ± 2.0%), and threshold for sentence-triggering (60.2 ± 16.3%). Conclusion: These error mechanisms raise interesting questions about the potential of automated report generation and the quality of image reading by humans. The most significant discrepancy between the human and automatically generated RRs was caused by the sentence-triggering threshold (the degree of abnormality), which was fixed to z-score >2.0 for the automated generation, while the thresholds by radiologists varied among different anatomical structures.

Objective : Limited studies exist on the association between loss of consciousness (LOC) and altered mental state (AMS) and development of depressive and post-concussive symptoms within six months after mild traumatic brain injury (mTBI). We tested the hypothesis that presence of both LOC and AMS predict the highest risk of symptoms within the first six months post-mTBI compared to either variable alone, and that LOC alone is more strongly associated with these symptoms. Research design : We analyzed data from 407 subjects with mTBI from the Head injury S erum M arkers for A ssessing R esponse to T rauma (HeadSMART) cohort, a prospective cohort of patients post-TBI presenting to two urban emergency departments. Results : There were higher rates of depressive (44%) and post-concussive symptoms (54%) at 1 month post-injury, among participants with both LOC and AMS compared to other groups. AMS was associated with depressive symptoms at one and six months (OR = 1.59, p = .038; OR = 1.60; p = .060) and post-concussive symptoms at one month (OR = 1.56, p = .053). LOC was associated only with post-concussive symptoms at one month (OR = 1.55;p = .048). Among those without LOC, AMS was associated with depressive symptoms at one month (OR = 2.24; p = .028). Conclusions : AMS predicts post-mTBI depressive symptoms both in the acute and chronic mTBI phases whereas LOC is a more sensitive predictor of post-concussive symptoms in the acute mTBI period.

ABSTRACTObjectives:Behavioral and psychological symptoms of dementia (BPSD) are nearly universal in dementia, a condition occurring in more than 40 million people worldwide. BPSD present a considerable treatment challenge for prescribers and healthcare professionals. Our purpose was to prioritize existing and emerging treatments for BPSD in Alzheimer's disease (AD) overall, as well as specifically for agitation and psychosis., Design: International Delphi consensus process. Two rounds of feedback were conducted, followed by an in-person meeting to ratify the outcome of the electronic process., Settings: 2015 International Psychogeriatric Association meeting., Participants: Expert panel comprised of 11 international members with clinical and research expertise in BPSD management., Results: Consensus outcomes showed a clear preference for an escalating approach to the management of BPSD in AD commencing with the identification of underlying causes. For BPSD overall and for agitation, caregiver training, environmental adaptations, person-centered care, and tailored activities were identified as first-line approaches prior to any pharmacologic approaches. If pharmacologic strategies were needed, citalopram and analgesia were prioritized ahead of antipsychotics. In contrast, for psychosis, pharmacologic options, and in particular, risperidone, were prioritized following the assessment of underlying causes. Two tailored non-drug approaches (DICE and music therapy) were agreed upon as the most promising non-pharmacologic treatment approaches for BPSD overall and agitation, with dextromethorphan/quinidine as a promising potential pharmacologic candidate for agitation. Regarding future treatments for psychosis, the greatest priority was placed on pimavanserin., Conclusions: This international consensus panel provided clear suggestions for potential refinement of current treatment criteria and prioritization of emerging therapies.

11 C-RO-963, 11 C-RO-643, and 18 F-RO-948 (previously referred to as 11 C-RO6924963, 11 C-RO6931643, and 18 F-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 11 C-RO-963, 11 C-RO-643, or 18 F-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 18 F-RO-948 for evaluation of test-retest variability. Four AD subjects underwent a repeated 18 F-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 18 F-RO-948. Results: In younger controls, SUV peak was observed in the temporal lobe with values of approximately 3.0 for 11 C-RO-963, 1.5 for 11 C-RO-643, and 3.5 for 18 F-RO-948. Over all brain regions and subjects, the trend was for 18 F-RO-948 to have the highest SUV peak , followed by 11 C-RO-963 and then 11 C-RO-643. Regional analysis of SUV ratio and total distribution volume for 11 C-RO-643 and 18 F-RO-948 clearly discriminated the AD group from the healthy control groups. Compartmental modeling confirmed that 11 C-RO-643 had lower brain entry than either 11 C-RO-963 or 18 F-RO-948 and that 18 F-RO-948 showed better contrast between (predicted) areas of high versus low tau accumulation. Thus, our subsequent analysis focused on 18 F-RO-948. Both voxelwise and region-based analysis of 18 F-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: 18 F-RO-948 demonstrates characteristics superior to 11 C-RO-643 and 11 C-RO-963 for characterization of tau pathology in AD. Regional binding data and kinetic properties of 18 F-RO-948 compare favorably with other existing tau PET tracers., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Importance: The Johns Hopkins Community Health Partnership was created to improve care coordination across the continuum in East Baltimore, Maryland., Objective: To determine whether the Johns Hopkins Community Health Partnership (J-CHiP) was associated with improved outcomes and lower spending., Design, Setting, and Participants: Nonrandomized acute care intervention (ACI) and community intervention (CI) Medicare and Medicaid participants were analyzed in a quality improvement study using difference-in-differences designs with propensity score-weighted and matched comparison groups. The study spanned 2012 to 2016 and took place in acute care hospitals, primary care clinics, skilled nursing facilities, and community-based organizations. The ACI analysis compared outcomes of participants in Medicare and Medicaid during their 90-day postacute episode with those of a propensity score-weighted preintervention group at Johns Hopkins Community Health Partnership hospitals and a concurrent comparison group drawn from similar Maryland hospitals. The CI analysis compared changes in outcomes of Medicare and Medicaid participants with those of a propensity score-matched comparison group of local residents., Interventions: The ACI bundle aimed to improve transition planning following discharge. The CI included enhanced care coordination and integrated behavioral support from local primary care sites in collaboration with community-based organizations., Main Outcomes and Measures: Utilization measures of hospital admissions, 30-day readmissions, and emergency department visits; quality of care measures of potentially avoidable hospitalizations, practitioner follow-up visits; and total cost of care (TCOC) for Medicare and Medicaid participants., Results: The CI group had 2154 Medicare beneficiaries (1320 [61.3%] female; mean age, 69.3 years) and 2532 Medicaid beneficiaries (1483 [67.3%] female; mean age, 55.1 years). For the CI group's Medicaid participants, aggregate TCOC reduction was $24.4 million, and reductions of hospitalizations, emergency department visits, 30-day readmissions, and avoidable hospitalizations were 33, 51, 36, and 7 per 1000 beneficiaries, respectively. The ACI group had 26 144 beneficiary-episodes for Medicare (13 726 [52.5%] female patients; mean patient age, 68.4 years) and 13 921 beneficiary-episodes for Medicaid (7392 [53.1%] female patients; mean patient age, 52.2 years). For the ACI group's Medicare participants, there was a significant reduction in aggregate TCOC of $29.2 million with increases in 90-day hospitalizations and 30-day readmissions of 11 and 14 per 1000 beneficiary-episodes, respectively, and reduction in practitioner follow-up visits of 41 and 29 per 1000 beneficiary-episodes for 7-day and 30-day visits, respectively. For the ACI group's Medicaid participants, there was a significant reduction in aggregate TCOC of $59.8 million and the 90-day emergency department visit rate decreased by 133 per 1000 episodes, but hospitalizations increased by 49 per 1000 episodes and practitioner follow-up visits decreased by 70 and 182 per 1000 episodes for 7-day and 30-day visits, respectively. In total, the CI and ACI were associated with $113.3 million in cost savings., Conclusions and Relevance: A care coordination model consisting of complementary bundled interventions in an urban academic environment was associated with lower spending and improved health outcomes.

The aim of this study was to describe sex differences in neuropsychiatric symptoms (NPSs) in patients with Alzheimer's disease (AD). Baseline scores on the Cohen-Mansfield Agitation Inventory, Neurobehavioral Rating Scale-Agitation subscale, and the Neuropsychiatric Inventory from patients with AD enrolled in a multicenter trial of citalopram for the treatment of agitation were analyzed. We found not only that patients with AD having agitation were likely to exhibit many other NPSs but also that the women in this study were more likely to exhibit a broader range of NPS than were the men. These results suggest greater heterogeneity in the clinical presentation of women compared to men, and thus in the potential targets for treatment in these patients. Further characterization of sex differences in NPS can inform future efforts aimed at establishing subtypes of patients for whom various treatment approaches will be most appropriate.

Purpose: Studies have reported faster cognitive/functional decline in persons with dementia (PWD) with malnutrition. We investigated whether baseline nutritional status predicted severe dementia and mortality in a population-based sample., Patients: A maximum of 300 PWD were assessed annually for up to 8.6 years., Methods: Nutritional status was assessed using a modified Mini-Nutritional Assessment (mMNA). Severe dementia was defined as: "severe" rating on the Clinical Dementia Rating or Mini-Mental State Examination score ≤10. Using Cox proportional hazards models, we examined the association between baseline mMNA score (or its subcomponents) with each outcome. Covariates included demographics; dementia onset age, type, and duration; APOE genotype; and residency with caregiver., Results: Compared with "well-nourished," "malnourished" PWD had 3-4 times the hazard of severe dementia [hazard ratio (HR), 4.31; P=0.014] and death (HR, 3.04; P<0.001). Those "at risk for malnutrition" had twice the hazard of severe dementia (HR, 1.98; P=0.064) and 1.5 times the hazard of death (HR, 1.46; P=0.015). mMNA subcomponents of food group intake, weight loss, body mass index, mobility, health status, protein consumption, and mid-arm circumference predicted one or both outcomes., Conclusions: Nutritional status is an important predictor of clinical outcomes in dementia and may provide an avenue for intervention.

ABSTRACTBackground:The use of FDA approved medications for Alzheimer's disease [AD; FDAAMAD; (cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists)] has been associated with symptomatic benefit with a reduction in formal (paid services) and total costs of care (formal and informal costs). We examined the use of these medications and their association with informal costs in persons with dementia., Method: Two hundred eighty participants (53% female, 72% AD) from the longitudinal, population-based Dementia Progression Study in Cache County, Utah (USA) were followed up to ten years. Mean (SD) age at baseline was 85.6 (5.5) years. Informal costs (expressed in 2015 dollars) were calculated using the replacement cost method (hours of care multiplied by the median wage in Utah in the visit year) and adjusted for inflation using the Medical Consumer Price Index. Generalized Estimating Equations with a gamma log-link function were used to examine the longitudinal association between use of FDAAMAD and informal costs., Results: The daily informal cost for each participant at baseline ranged from $0 to $318.12, with the sample median of $9.40. Within the entire sample, use of FDAAMAD was not significantly associated with informal costs (expβ = 0.73, p = 0.060). In analyses restricted to participants with mild dementia at baseline (N = 222), use of FDAAMAD was associated with 32% lower costs (expβ = 0.68, p = 0.038)., Conclusions: Use of FDAAMAD was associated with lower informal care costs in those with mild dementia only.

Background: There is strong association of Alzheimer's disease (AD) pathology with gait disorder and falls in older adults without dementia. The goal of the study was to examine the prevalence and severity of AD pathology in older adults without dementia who fall and sustain hip fracture., Methods: Cerebrospinal fluid (CSF) was obtained from 168 hip fracture patients. CSF Aβ42/40 ratio, p-tau, and t-tau measures were dichotomized into normal vs. abnormal, and categorized according to the A/T/N classification., Results: Among the hip fracture patients, 88.6% of the cognitively normal (Clinical Dementia Rating-CDR 0; n = 70) and 98.8% with mild cognitive impairment (CDR 0.5; n = 81) fell in the abnormal biomarker categories by the A/T/N classification., Conclusions: A large proportion of older hip fracture patients have CSF evidence of AD pathology. Preoperative determination of AD biomarkers may play a crucial role in identifying persons without dementia who have underlying AD pathology in perioperative settings., Competing Interests: In addition, we had previously stated in the Competing Interests section that one of our co-authors Dr. Zetterberg is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenberg, and has served at advisory boards of Roche Diagnostics and Eli Lilly and has received travel support from TEVA. We confirm that this does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose Academic healthcare systems face great challenges in coordinating services across a continuum of care that spans hospital, community providers, home and chronic care facilities. The Johns Hopkins Community Health Partnership (J-CHiP) was created to improve coordination of acute, sub-acute and ambulatory care for patients, and improve the health of high-risk patients in surrounding neighborhoods. The paper aims to discuss this issue. Design/methodology/approach J-CHiP targeted adults admitted to the Johns Hopkins Hospital and Johns Hopkins Bayview Medical Center, patients discharged to participating skilled nursing facilities (SNFs), and high-risk Medicare and Medicaid patients receiving primary care in eight nearby outpatient sites. The primary drivers of the program were redesigned acute care delivery, seamless transitions of care and deployment of community care teams. Findings Acute care interventions included risk screening, multidisciplinary care planning, pharmacist-driven medication management, patient/family education, communication with next provider and care coordination protocols for common conditions. Transition interventions included post-discharge health plans, hand-offs and follow-up with primary care providers, Transition Guides, a patient access line and collaboration with SNFs. Community interventions involved forming multidisciplinary care coordination teams, integrated behavioral care and new partnerships with community-based organizations. Originality/value This paper offers a detailed description of the design and implementation of a complex program to improve care coordination for high-risk patients in an urban setting. The case studies feature findings from each intervention that promoted patient engagement, strengthened collaboration with community-based organizations and improved coordination of care.

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Many older adults living with dementia have not been formally diagnosed. Even when clinicians document the diagnosis, patients and families may be unaware of the diagnosis. Knowledge of how individual characteristics affect detection and awareness of dementia is limited., Objective: To identify characteristics associated with dementia diagnosis and awareness of diagnosis., Design: Cross-sectional observational study., Participants: Five hundred eighty-five adults aged ≥ 65 in the National Health and Aging Trends Study who met assessment-based study criteria for probable dementia in 2011 and had 3 years of continuous, fee-for-service Medicare claims prior to 2011., Main Measures: Using multivariable logistic regression, we compared participants with undiagnosed versus diagnosed dementia (based on Medicare claims) on demographic, social/behavioral, functional, medical, and healthcare utilization characteristics. Among those diagnosed, we compared characteristics of participants unaware versus aware of the diagnosis (based on self or proxy report)., Key Results: Among older adults with probable dementia, 58.7% were either undiagnosed (39.5%) or unaware of the diagnosis (19.2%). In adjusted analyses, individuals who were Hispanic (OR 2.48, 95% CI 1.19, 5.14), had less than high school education (OR 0.54 for at least high school education, 95% CI 0.32, 0.91), attended medical visits alone (OR 1.98, 95% CI 1.11, 3.51), or had fewer functional impairments (OR 0.79 for each impairment, 95% CI 0.69, 0.90) were more likely to be undiagnosed. Similarly, among those diagnosed, having less education (OR 0.42), attending medical visits alone (OR 1.97), and fewer functional impairments (OR 0.72) were associated with unawareness of diagnosis (all ps < 0.05)., Conclusions: The majority of older adults with dementia are either undiagnosed or unaware of the diagnosis, suggesting shortcomings in detection and communication of dementia. Individuals who may benefit from targeted screening include racial/ethnic minorities and persons who have lower educational attainment, any functional impairment, or attend medical visits alone.

Background: Behavioral and psychological symptoms of dementia (BPSD) are universal and associated with multiple negative outcomes. This pilot randomized controlled trial (RCT) evaluated the effect of using the WeCareAdvisor, an innovative web-based tool developed to enable family caregivers to assess, manage, and track BPSD., Methods: This RCT enrolled 57 dementia family caregivers from community and clinical settings in Ann Arbor, Michigan and Baltimore, Maryland. Participants were randomly assigned to immediate use of the WeCareAdvisor tool (WCA, n = 27) or a Waitlist control group (n = 30) that received the tool after a one-month waiting period. Outcomes for the caregiver and the person they were caring for were assessed at baseline (T0) and one-month followup for both the WCA (T1) and Waitlist control (T2) groups., Results: Caregiver mean age was 65.9 ± 14.0 years old. About half (49%) were spouses. Baseline characteristics were comparable between groups except for mean caregiver confidence which was higher in the control group (WCA 35.0 ± 10.0 vs. Waitlist control 39.7 ± 6.9, p = 0.04). There were no significant differences between the WCA and control groups in characteristics of the person with dementia. After their one-month of tool use (T1), WCA caregivers showed significant within group improvement in caregiver distress (- 6.08 ± 6.31 points, t = - 4.82, p < 0.0001) and behavioral frequency (- 3.60 ± 5.05, t = - 3.56, p = 0.002), severity (- 3.24 ± 3.87, t = - 4.19, p = 0.0003) and total behavioral score (- 6.80 ± 10.73, t = - 3.17, p = 004). In the same timeframe, Waitlist control caregivers showed a significant decrease in confidence (- 6.40 ± 10.30, t = - 3.40, p = 0.002). The WCA group showed greater improvement in distress compared to the Waitlist group (T0-T1; t = - 2.49, p = 0.02), which remained significant after adjusting for site and baseline distress. There were no significant between-group differences in caregiver confidence or other secondary outcomes. After their one month of tool use (T2), the Waitlist group also showed significant improvement in caregiver distress (- 3.72 ± 7.53, t = - 2.66, p = 0.013), stress (- 0.41 ± 1.02, t = - 2.19, p = 0.037), confidence (4.38 ± 5.17, t = 4.56, p < 0.0001), burden (- 2.76 ± 7.26, t = - 2.05, p = 0.05), negative communication (- 1.48 ± 2.96, t = - 2.70, p = 0.012) and behavioral frequency (- 1.86 ± 4.58, t = - 2.19, p = 0.037); distress remained significant after adjustment., Conclusions: In this pilot RCT, WCA use resulted in a significant decrease in caregiver distress. Future research will identify whether longer use of WCA can impact other caregiver and behavioral outcomes., Trial Registration: Clinicaltrials.gov identifier NCT02420535 (Date of registry: 4/20/2015, prior to the start of the clinical trial).

Objective: To investigate effects of a novel dementia care coordination program on health services utilization., Data Sources/study Setting: A total of 303 community-dwelling adults aged ≥70 with a cognitive disorder in Baltimore, Maryland (2008-2011)., Study Design: Single-blind RCT evaluating efficacy of an 18-month care coordination intervention delivered through community-based nonclinical care coordinators, supported by an interdisciplinary clinical team., Data Collection/extraction Methods: Study partners reported acute care/inpatient, outpatient, and home- and community-based service utilization at baseline, 9, and 18 months., Principal Findings: From baseline to 18 months, there were no significant group differences in acute care/inpatient or total outpatient services use, although intervention participants had significantly increased outpatient dementia/mental health visits from 9 to 18 months (p = .04) relative to controls. Home and community-based support service use significantly increased from baseline to 18 months in the intervention compared to control (p = .005)., Conclusions: While this dementia care coordination program did not impact acute care/inpatient services utilization, it increased use of dementia-related outpatient medical care and nonmedical supportive community services, a combination that may have helped participants remain at home longer. Future care model modifications that emphasize delirium, falls prevention, and behavior management may be needed to influence inpatient service use., (© Health Research and Educational Trust.)

Introduction: A national consensus panel was convened to develop recommendations on future directions for home-based dementia care (HBDC)., Methods: The panel summarized advantages and challenges of shifting to HBDC as the nexus of care and developed consensus-based recommendations., Results: The panel developed five core recommendations: (1) HBDC should be considered the nexus of new dementia models, from diagnosis to end of life in dementia; (2) new payment models are needed to support HBDC and reward integration of care; (3) a diverse new workforce that spans the care continuum should be prepared urgently; (4) new technologies to promote communication, monitoring/safety, and symptoms management must be tested, integrated, and deployed; and (5) targeted dissemination efforts for HBDC must be employed., Discussion: HBDC represents a promising paradigm shift to improve care for those living with dementia and their family caregivers: these recommendations provide a framework to chart a course forward for HBDC., (Copyright © 2017 the Alzheimer's Association. All rights reserved.)

Objectives: The purpose of this study was to assess whether study population definition influences the effect of age on outcomes after blunt head trauma. We hypothesized that examining 'all comers' receiving head computerized tomography after blunt head trauma, fewer older individuals would meet Veterans Administration and Department of Defense (VA/DoD) criteria for traumatic brain injury (TBI), and would, therefore, display better outcomes than younger cohorts. However, restricting to participants meeting VA/DoD criteria for TBI, we hypothesized that older individuals would have worse outcomes., Methods: Data from a recently completed prospective cohort study were analysed with age dichotomized at 65 years. Logistic regression modelling, controlled for potential confounders including head trauma severity, was estimated to measure the effect of age on functional recovery, post-concussion symptoms (PCS), and depressive symptoms at 1-month post-TBI., Results: Fewer older than younger individuals met VA/DoD criteria for TBI. Older individuals had better functional, PCS, and depressive outcomes at 1 month. Restricting to those meeting VA/DoD criteria for TBI, older individuals continued to have better functional and PCS outcomes but had outcomes comparable to younger on depressive symptoms., Conclusions: Contrary to our hypothesis, there was a tendency for older adults to have better outcomes than younger, independent of the diagnostic criteria applied.

Background: Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants≥65 years., Objective: To examine the long-term safety and clinical effects of sustained and delayed-on DBS-f treatment of mild AD after two years., Methods: 42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial., Results: DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants., Conclusion: DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65.

Background: To date, the therapeutic paradigm for Alzheimer's disease (AD) has focused on a single intervention for all patients. However, a large literature in oncology supports the therapeutic benefits of a precision medicine approach to therapy. Here we test a precision-medicine approach to AD therapy., Objective: To determine if a baseline, blood-based proteomic companion diagnostic predicts response to NSAID therapy., Methods: Proteomic assays of plasma from a multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to rofecoxib (25 mg once daily), naproxen (220 mg twice-daily) or placebo., Results: 474 participants with mild-to-moderate AD were screened with 351 enrolled into the trial. Using support vector machine (SVM) analyses, 89% of the subjects randomized to either NSAID treatment arms were correctly classified using a general NSAID companion diagnostic. Drug-specific companion diagnostics yielded 98% theragnostic accuracy in the rofecoxib arm and 97% accuracy in the naproxen arm., Conclusion: Inflammatory-based companion diagnostics have significant potential to identify select patients with AD who have a high likelihood of responding to NSAID therapy. This work provides empirical support for a precision medicine model approach to treating AD.

Introduction: Despite availability of effective care strategies for dementia, most health care systems are not yet organized or equipped to provide comprehensive family-centered dementia care management. Maximizing Independence at Home-Plus is a promising new model of dementia care coordination being tested in the U.S. through a Health Care Innovation Award funded by the Centers for Medicare and Medicaid Services that may serve as a model to address these delivery gaps, improve outcomes, and lower costs. This report provides an overview of the Health Care Innovation Award aims, study design, and methodology., Methods: This is a prospective, quasi-experimental intervention study of 342 community-living Medicare-Medicaid dual eligibles and Medicare-only beneficiaries with dementia in Maryland. Primary analyses will assess the impact of Maximizing Independence at Home-Plus on risk of nursing home long-term care placement, hospitalization, and health care expenditures (Medicare, Medicaid) at 12, 18 (primary end point), and 24 months, compared to a propensity-matched comparison group., Discussion: The goals of the Maximizing Independence at Home-Plus model are to improve care coordination, ability to remain at home, and life quality for participants and caregivers, while reducing total costs of care for this vulnerable population. This Health Care Innovation Award project will provide timely information on the impact of Maximizing Independence at Home-Plus care coordination model on a variety of outcomes including effects on Medicaid and Medicare expenditures and service utilization. Participant characteristic data, cost savings, and program delivery costs will be analyzed to develop a risk-adjusted payment model to encourage sustainability and facilitate spread., Competing Interests: Declaration of conflicting interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Under a license agreement between Mind Halo, Inc. and the Johns Hopkins University, and Drs. Lyketsos, Black, and Johnston are entitled to royalties and equity on technology described in this publication. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies.

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10 -4 ) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10 -8 ) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10 -10 , odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 -10 , OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 -14 , OR = 1.67, MAF cases = 0.0143, MAF controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Background/objectives: Behavioral and psychological symptoms of dementia (BPSD) are nearly universal in dementia and associated with multiple negative outcomes. Current real-world management is largely pharmacologic, despite poor risk/benefit. The WeCareAdvisor was designed to enable family caregivers to assess, manage, and track BPSD using nonpharmacologic strategies., Design: In-depth qualitative data were collected from family caregivers of people with dementia to inform: (1) style of approach and "look and feel" of the tool, and (2) the types of psychoeducation most needed by caregivers., Results: We conducted 4 focus groups and a technology survey (n=26) as well as additional individual semistructured interviews (n=12) with family caregivers. Main themes of the qualitative work included: (1) need to minimize difficulty and training time; (2) importance of "one-stop shopping" for information; and (3) necessity for information to be tailored to the caregiver and person with dementia. This information was then combined with effective existing evidence-based behavioral strategies to create a web-based tailored caregiver-support tool., Conclusions: The WeCareAdvisor was designed with input on functionality and content by end-users, family caregivers. The randomized controlled trial of WeCareAdvisor will test whether the tool improves outcomes including caregiver upset and burden and frequency and severity of BPSD.

Physicians and patients may choose a certain treatment only if it is predicted to have a large effect for the profile of that patient. We consider randomized controlled trials in which the clinical goal is to identify as many patients as possible that can highly benefit from the treatment. This is challenging with large numbers of covariate profiles, first, because the theoretical, exact method is not feasible, and, second, because usual model-based methods typically give incorrect results. Better, more recent methods use a two-stage approach, where a first stage estimates a working model to produce a scalar predictor of the treatment effect for each covariate profile; and a second stage estimates empirically a high-benefit group based on the first-stage predictor. The problem with these methods is that each of the two stages is usually agnostic about the role of the other one in addressing the clinical goal. We propose a method that characterizes highly benefited patients by linking model estimation directly to the particular clinical goal. It is shown that the new method has the following two key properties in comparison with existing approaches: first, the meaning of the solution with regard to the clinical goal is the same, and second, the value of the solution is the best that can be achieved when using the working model as a predictor, even if that model is incorrect. In the Citalopram for Agitation in Alzheimer's Disease (CitAD) randomized controlled trial, the new method identifies substantially larger groups of highly benefited patients, many of whom are missed by the standard method.

Importance: Microglia, the resident immune cells of the central nervous system, play an important role in the brain's response to injury and neurodegenerative processes. It has been proposed that prolonged microglial activation occurs after single and repeated traumatic brain injury, possibly through sports-related concussive and subconcussive injuries. Limited in vivo brain imaging studies months to years after individuals experience a single moderate to severe traumatic brain injury suggest widespread persistent microglial activation, but there has been little study of persistent glial cell activity in brains of athletes with sports-related traumatic brain injury., Objective: To measure translocator protein 18 kDa (TSPO), a marker of activated glial cell response, in a cohort of National Football League (NFL) players and control participants, and to report measures of white matter integrity., Design, Setting, and Participants: This cross-sectional, case-control study included young active (n = 4) or former (n = 10) NFL players recruited from across the United States, and 16 age-, sex-, highest educational level-, and body mass index-matched control participants. This study was conducted at an academic research institution in Baltimore, Maryland, from January 29, 2015, to February 18, 2016., Main Outcomes and Measures: Positron emission tomography-based regional measures of TSPO using [11C]DPA-713, diffusion tensor imaging measures of regional white matter integrity, regional volumes on structural magnetic resonance imaging, and neuropsychological performance., Results: The mean (SD) ages of the 14 NFL participants and 16 control participants were 31.3 (6.1) years and 27.6 (4.9) years, respectively. Players reported a mean (SD) of 7.0 (6.4) years (range, 1-21 years) since the last self-reported concussion. Using [11C]DPA-713 positron emission tomographic data from 12 active or former NFL players and 11 matched control participants, the NFL players showed higher total distribution volume in 8 of the 12 brain regions examined (P < .004). We also observed limited change in white matter fractional anisotropy and mean diffusivity in 13 players compared with 15 control participants. In contrast, these young players did not differ from control participants in regional brain volumes or in neuropsychological performance., Conclusions and Relevance: The results suggest that localized brain injury and repair, indicated by higher TSPO signal and white matter changes, may be associated with NFL play. Further study is needed to confirm these findings and to determine whether TSPO signal and white matter changes in young NFL athletes are related to later onset of neuropsychiatric symptoms.

Background: Cellular and animal studies demonstrated relationships between sphingolipid metabolism and Alzheimer's disease (AD) pathology. High blood ceramide levels have been shown to predict cognitive impairment and AD, but these studies had small sample sizes and did not assess differences in risk by sex or APOE genotype., Objective: To determine whether plasma ceramides and sphingomyelins were associated with risk of AD, and whether the association varied by sex and APOE genotype., Methods: Participants included 626 men and 366 women, aged 55 years and older, enrolled in the Baltimore Longitudinal Study of Aging. Plasma ceramides and sphingomyelins were determined using quantitative analyses performed on a high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometer. Cox proportional hazards models, stratified by sex, were used to examine the relationship of plasma ceramides and sphingomyelins with risk of AD over a mean (SD) follow-up of 15.0 (7.0) years for men and 13.1 (5.9) years for women., Results: Among men, the highest tertile of most ceramides and sphingomyelins were associated with an increased risk of AD. Among women, there were no associations between any of the ceramides and risk of AD. In contrast, women in the highest tertile of most sphingomyelins had a reduced risk of AD, which was most pronounced among APOE ɛ4 carriers., Conclusion: These results provide further evidence for the role of sphingolipid metabolism in AD and highlight the importance of considering sex and APOE genotype in assessing this relationship.

Background: Accurate diagnosis and risk stratification of traumatic brain injury (TBI) at time of presentation remains a clinical challenge. The Head Injury Serum Markers for Assessing Response to Trauma study (HeadSMART) aims to examine blood-based biomarkers for diagnosing and determining prognosis in TBI., Methods: HeadSMART is a 6-month prospective cohort study comparing emergency department patients evaluated for TBI (exposure group) to (1) emergency department patients evaluated for traumatic injury without head trauma and (2) healthy persons. Study methods and characteristics of the first 300 exposure participants are discussed., Results: Of the first 300 participants in the exposure arm, 70% met the American Congress of Rehabilitation Medicine criteria for TBI, with the majority (80.1%) classified as mild TBI. The majority of subjects in the exposure arm had Glasgow Coma Scale scores of 13-15 (98.0%), normal head computed tomography (81.3%) and no prior history of concussion (71.7%)., Conclusion: With systematic phenotyping, HeadSMART will facilitate diagnosis and risk-stratification of the heterogeneous group of individuals currently diagnosed with TBI.

Objective: Depression may be a prodrome to Alzheimer's disease (AD). We assessed whether AD neuropathology is associated with depression in mild cognitive impairment (MCI) and mild dementia (dAD)., Methods: All clinical and neuropathological data for this study came from the National Alzheimer's Coordinating Center (NACC). Healthy control (HC, n = 120), MCI (n = 77), and mild dAD (n = 93) patients who underwent brain autopsy were included. In regression models with Geriatric Depression Scale (GDS) as the outcome, neuritic plaque (NP) score or Braak Stages of neurofibrillary (NF) pathology were covariates., Results: GDS was not associated with cognitive status, NP score, Braak Stages, or their interaction. In both models, a history of TIAs, depression within the last 2 years, current benzodiazepine use, and greater severity of neuropsychiatric symptoms were associated with greater depression. In the Braak Stages model, less education was another significant predictor., Conclusions: Depression in early AD appears to be independent of NP and NF pathology. Studies are needed to investigate other mechanisms that may be responsible for depression in MCI and dAD., (Copyright © 2016 John Wiley & Sons, Ltd.)

Introduction: The preponderance of dementia among postmenopausal women compared with same-age men and the female sex hormones neuroprotective properties support a tentative role of their deficiency in the dementia pathogenesis., Methods: Pairs of independent reviewers screened 12,323 publications derived from a search strategy for MEDLINE to identify articles investigating the association of age at menopause/reproductive period with (i) dementia and (ii) cognitive function; a snowball of eligible articles and reviews was conducted and authors were contacted for additional information. Random-effect models were used for the meta-analysis., Results: Age at menopause (13 studies; 19,449 participants) and reproductive period (4 studies; 9916 participants) in the highest categories were not associated with odds of dementia (effect size [ES]: 0.97 [0.78-1.21]) and Alzheimer's disease (ES: 1.06 [0.71-1.58]). Significant heterogeneity was however noted in both analyses (I 2 : 63.3%, p=0.003 and I 2 : 72.6%, p=0.01, respectively). Subgroup analyses by outcome assessment, study design, level of adjustment and study quality did not materially change the findings. In 9/13 studies assessing cognitive function, advanced age at menopause/longer reproductive period was significantly associated with better cognitive performance/lower decline. Due to statistical differences, no meta-analysis was possible for cognitive function., Conclusions: Existing evidence does not support an association between indices of prolonged exposure to female hormones and lower dementia risk. There are indications, however, for better cognitive performance and delayed cognitive decline, supporting a link between female hormone deficiency and cognitive aging. Current literature limitations, indicated by the heterogeneous study-set, point towards research priorities in this clinically relevant area., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Deep brain stimulation (DBS) is used to modulate the activity of dysfunctional brain circuits. The safety and efficacy of DBS in dementia is unknown., Objective: To assess DBS of memory circuits as a treatment for patients with mild Alzheimer's disease (AD)., Methods: We evaluated active "on" versus sham "off" bilateral DBS directed at the fornix-a major fiber bundle in the brain's memory circuit-in a randomized, double-blind trial (ClinicalTrials.gov NCT01608061) in 42 patients with mild AD. We measured cognitive function and cerebral glucose metabolism up to 12 months post-implantation., Results: Surgery and electrical stimulation were safe and well tolerated. There were no significant differences in the primary cognitive outcomes (ADAS-Cog 13, CDR-SB) in the "on" versus "off" stimulation group at 12 months for the whole cohort. Patients receiving stimulation showed increased metabolism at 6 months but this was not significant at 12 months. On post-hoc analysis, there was a significant interaction between age and treatment outcome: in contrast to patients <65 years old (n = 12) whose results trended toward being worse with DBS ON versus OFF, in patients≥65 (n = 30) DBS-f ON treatment was associated with a trend toward both benefit on clinical outcomes and a greater increase in cerebral glucose metabolism., Conclusion: DBS for AD was safe and associated with increased cerebral glucose metabolism. There were no differences in cognitive outcomes for participants as a whole, but participants aged≥65 years may have derived benefit while there was possible worsening in patients below age 65 years with stimulation.

Introduction: Identifying factors associated with lower dementia care costs is essential. We examined whether two caregiver factors were associated with lower costs of informal care., Methods: A total of 271 care dyads of the Cache County Dementia Study were included. Estimates of informal costs were based on caregiver reports of time spent in care-related activities and inflation-adjusted 2012 Utah median hourly wages. Caregiver coping and emotional closeness with the care-recipient were assessed using the Ways of Coping Checklist-Revised and Relationship Closeness Scale, respectively., Results: Higher closeness was associated with 24% lower costs (expβ = 0.763 [95% confidence interval: 0.583-0.999]) in linear mixed models controlling for demographics and baseline dementia severity and duration. Problem-focused coping was not associated with informal costs (P = .354)., Discussion: Caregiver closeness, a potentially modifiable factor, predicted lower dementia informal care costs over time. Future studies examining the care environment in closer dyads may identify specific care-related behaviors or strategies that are associated with lower costs., (Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Background: We developed a composite measure of agitation as a secondary outcome of change over time in the Citalopram for Agitation in Alzheimer's disease study (CitAD). CitAD demonstrated a positive effect of citalopram on agitation on the Neurobehavioral Rating Scale agitation subscale (NBRS-A). CitAD included additional agitation measures such as the Cohen-Mansfield Agitation Inventory and the Neuropsychiatric Inventory., Methods: We performed principal components analyses on change in individual item of these scales for the same, original CitAD subjects., Results: The first principal component accounted for 12.6% of the observed variance and was composed of items that appear to reflect agitation. The effect size for citalopram calculated using this component was 0.53 (95% CI 0.22-0.83) versus 0.32 for the NBRS-A (95% CI 0.01-0.62)., Conclusions: Results suggest that a composite measure of change in agitation might be more sensitive than change in a single primary agitation measure., (Published by Elsevier Ltd.)

OBJECT This report describes the stereotactic technique, hospitalization, and 90-day perioperative safety of bilateral deep brain stimulation (DBS) of the fornix in patients who underwent DBS for the treatment of mild, probable Alzheimer's disease (AD). METHODS The ADvance Trial is a multicenter, 12-month, double-blind, randomized, controlled feasibility study being conducted to evaluate the safety, efficacy, and tolerability of DBS of the fornix in patients with mild, probable AD. Intraoperative and perioperative data were collected prospectively. All patients underwent postoperative MRI. Stereotactic analyses were performed in a blinded fashion by a single surgeon. Adverse events (AEs) were reported to an independent clinical events committee and adjudicated to determine the relationship between the AE and the study procedure. RESULTS Between June 6, 2012, and April 28, 2014, a total of 42 patients with mild, probable AD were treated with bilateral fornix DBS (mean age 68.2 ± 7.8 years; range 48.0-79.7 years; 23 men and 19 women). The mean planned target coordinates were x = 5.2 ± 1.0 mm (range 3.0-7.9 mm), y = 9.6 ± 0.9 mm (range 8.0-11.6 mm), z = -7.5 ± 1.2 mm (range -5.4 to -10.0 mm), and the mean postoperative stereotactic radial error on MRI was 1.5 ± 1.0 mm (range 0.2-4.0 mm). The mean length of hospitalization was 1.4 ± 0.8 days. Twenty-six (61.9%) patients experienced 64 AEs related to the study procedure, of which 7 were serious AEs experienced by 5 patients (11.9%). Four (9.5%) patients required return to surgery: 2 patients for explantation due to infection, 1 patient for lead repositioning, and 1 patient for chronic subdural hematoma. No patients experienced neurological deficits as a result of the study, and no deaths were reported. CONCLUSIONS Accurate targeting of DBS to the fornix without direct injury to it is feasible across surgeons and treatment centers. At 90 days after surgery, bilateral fornix DBS was well tolerated by patients with mild, probable AD. Clinical trial registration no.: NCT01608061 ( clinicaltrials.gov ).

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Citalopram has been shown to improve agitation in patients with Alzheimer's disease. The authors evaluated whether other neuropsychiatric symptoms improve with citalopram treatment compared with placebo., Method: In this planned secondary analysis of the Citalopram for Agitation in Alzheimer's Disease study, the authors evaluated the effect of citalopram on the 12 neuropsychiatric symptom domains assessed by the Neuropsychiatric Inventory (NPI). They compared caregiver-reported NPI scores at week 9 in patients receiving citalopram (30 mg/day) or placebo with regard to both the presence or absence of individual neuropsychiatric symptoms and individual domain scores (reflecting severity) in participants who had symptoms at week 9., Results: At week 9, participants treated with citalopram were significantly less likely to be reported as showing delusions (odds ratio=0.40), anxiety (odds ratio=0.43), and irritability/lability (odds ratio=0.38). A comparison of median scores of participants with symptoms present at week 9 showed significant differences favoring citalopram for hallucinations and favoring placebo for sleep/nighttime behavior disorders., Conclusions: While dosage constraints must be considered because of citalopram's adverse effect profile, this agent's overall therapeutic effects in patients with Alzheimer's disease and agitation, in addition to efficacy for agitation/aggression, included reductions in the frequency of irritability, anxiety, and delusions; among patients who had these symptoms at week 9, they included a reduction in the severity of hallucinations but an increase in the severity of sleep/nighttime behavior disorders.

Objective: Pharmacological treatments for agitation and aggression in patients with Alzheimer's disease have shown limited efficacy. The authors assessed the heterogeneity of response to citalopram in the Citalopram for Agitation in Alzheimer Disease (CitAD) study to identify individuals who may be helped or harmed., Method: In this double-blind parallel-group multicenter trial of 186 patients with Alzheimer's disease and clinically significant agitation, participants were randomly assigned to receive citalopram or placebo for 9 weeks, with the dosage titrated to 30 mg/day over the first 3 weeks. Five planned potential predictors of treatment outcome were assessed, along with six additional predictors. The authors then used a two-stage multivariate method to select the most likely predictors; grouped participants into 10 subgroups by their index scores; and estimated the citalopram treatment effect for each., Results: Five covariates were likely predictors, and treatment effect was heterogeneous across the subgroups. Patients for whom citalopram was more effective were more likely to be outpatients, have the least cognitive impairment, have moderate agitation, and be within the middle age range (76-82 years). Patients for whom placebo was more effective were more likely to be in long-term care, have more severe cognitive impairment, have more severe agitation, and be treated with lorazepam., Conclusions: Considering several covariates together allowed the identification of responders. Those with moderate agitation and with lower levels of cognitive impairment were more likely to benefit from citalopram, and those with more severe agitation and greater cognitive impairment were at greater risk for adverse responses. Considering the dosages used and the association of citalopram with cardiac QT prolongation, use of this agent to treat agitation may be limited to a subgroup of people with dementia.