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Over the last few years, US Food and Drug Administration-approved drugs using RNA interference have come to the market. Many have treated liver-specific diseases utilizing N-acetyl galactosamine conjugation because of its effective delivery and limited off-target effects. The autosomal recessive disorder primary hyperoxaluria, specifically type 1, has benefited from these developments. Primary hyperoxaluria arises from mutations in the enzymes involved in endogenous oxalate synthesis. The severity of disease varies but can result in kidney failure and systemic oxalosis. Until recently, the treatment options were limited and focused primarily on supportive treatments, pyridoxine use in a subset of patients with primary hyperoxaluria type 1, and liver-kidney transplants in those who progressed to kidney failure. Two genes have been targeted with RNA interference; lumasiran targets glycolate oxidase and nedosiran targets lactate dehydrogenase A. Lumasiran was recently approved in the treatment of primary hyperoxaluria type 1 and nedosiran is in the approval process. Unfortunately, despite initial hopes that nedosiran may also be a treatment option for primary hyperoxaluria types 2 and 3, initial data suggest otherwise. The use of RNA interference liver-specific targeting for the treatment of primary hyperoxaluria type 1 will likely transform the natural history of the disease.

Objective Financial incentives may have utility in promoting psychotherapy attendance and adherence, leading to improved clinical functioning. This study presents results from a novel application of financial incentives—a progressively lowered pay scale that rewards therapy attendance and adherence. Method Overall, 110 outpatients participated; 56 patients (51%) were enrolled in the financial incentives condition and received a 5% fee discount—applied iteratively across sessions—if they followed defined criteria (e.g., completed homework). Results There were no statistically significant differences between groups in terms of the number of sessions attended, therapy duration, and number of no-shows and cancellations. However, adjusting for Global Assessment of Functioning (GAF) at intake, patients receiving the financial incentives had significantly higher GAF rating at termination compared with those who did not receive the intervention. Conclusions Financial incentives that reward therapy attendance and adherence with discounted fees is associated with improved clinical functioning.

To examine headache trajectories among persons with mild traumatic brain injury (MTBI) in the year after injury and the relation of headache trajectory to posttraumatic stress disorder (PTSD) at 1 year postinjury.Prospective, longitudinal study.Participants were recruited through a university medical center and participated in follow-up assessments by telephone.Prospectively enrolled individuals (N=212) within 1 week of MTBI who were hospitalized for observation or other system injuries. Participants were assessed at baseline and 3, 6, and 12 months postinjury.Not applicable.Participants rated average headache pain intensity using the 0 to 10 numerical rating scale at each assessment period. The PTSD Checklist-Civilian Version was completed at 12 months postinjury.Latent class growth analysis produced a 4-trajectory group model, with groups labeled resolved, worsening, improving, and chronic. Multivariate regression modeling revealed that younger age and premorbid headache correlated with membership in the worse trajectory groups (worsening and chronic; P.001). Univariate regression revealed a significant association between PTSD and membership in the worse trajectory groups (P.001).Headache is common in the year after MTBI, with younger people, persons who previously had headaches, and persons with PTSD more likely to report chronic or worsening headache. Further research is needed to examine whether PTSD symptoms exacerbate headaches or whether problematic headache symptoms exacerbate PTSD.

Objective To assess the prevalence of pain, depression, and comorbid pain and depression among a civilian sample of persons with traumatic brain injury (TBI). Design Longitudinal survey design with 1-year follow-up. Setting Inpatient rehabilitation and the community. Participants Participants (N=158) admitted to inpatient rehabilitation after moderate to severe TBI. Interventions Not applicable. Main Outcome Measures Depression was assessed with the Patient Health Questionnaire-9 (PHQ-9); pain was assessed with a numerical rating scale from 0 (no pain) to 10 (worst pain). Participants who reported average pain ≥4 were classified as having pain, and participants with PHQ-9 scores ≥10 were classified as depressed. Results Both pain and depression were more prevalent at baseline assessment (pain: 70%; depression: 31%) than at year 1 (pain: 34%; depression: 22%). Comorbid pain and depression declined from 27% at baseline to 18% at year 1. Pain was significantly associated with depression at baseline (relative risk: 2.62, P =.003) and at year 1 (relative risk: 7.98, P Conclusions Pain and depression are common and frequently co-occur in persons with TBI. Although their frequency declined over the first year after injury, the strength of their association increased. Assessment and treatment of both conditions simultaneously may lead to improved outcomes, both early after TBI and over time.

Objectives: Studies suggest early-onset depression (EOD) is associated with a more severe course of the depressive disorder, while late-onset depression (LOD) is associated with more cognitive and neuroimaging changes. This study examined if older adults with EOD, compared with those with LOD, would exhibit more severe symptoms of depression and, consistent with the glucocorticoid cascade hypothesis, have more hippocampal volume loss. A second goal was to determine if LOD, compared with EOD, would demonstrate more cognitive and neuroimaging changes. Method: At regular intervals over a four-year period non-demented, older, depressed adults were assessed on the Mini-Mental Status Examination and the Montgomery–Asberg Depression Rating Scale. They were also assessed on magnetic resonance imaging. Results: Compared with LOD, EOD had more depressive symptoms, more suicidal thoughts, and less social support. Growth curve analyses indicated that EOD demonstrated higher levels of residual depressive symptoms over time. The LOD group exhibited a greater decrement in cognitive scores. Contrary to the glucocorticoid cascade hypothesis, participants with EOD lost right hippocampal volume at a slower rate than did participants with LOD. Right cerebrum gray matter was initially smaller among participants with LOD. Conclusions: EOD is associated with greater severity of depressive illness. LOD is associated with more severe cognitive and neurological changes. These differences are relevant to understanding cognitive impairment in geriatric depression.

The aim of this study was to develop and test a model of depression, hippocampal changes, and cognitive decline.Participants were 248 community-dwelling, depressed patients and 147 healthy, non-depressed individuals 60 years and older. Participants received a structured interview assessing current depressive symptoms and past depressive episodes, completed cognitive testing with the Mini Mental State Examination (MMSE), and underwent structural Magnetic Resonance Imaging (MRI) of the brain. For up to 10 years, assessment of depressive symptoms and MMSE administration was repeated at least annually, and MRI was repeated every two years.Regression analyses demonstrated that depression diagnosis at baseline predicted decrease in right (but not left) hippocampal volume over a four-year period. Analyses using structural equation modeling demonstrated that a decrease in left and right hippocampal volumes predicted decrease in MMSE score over four years.Results provide some evidence for relationships between depression and decrease in right hippocampal volume, and between hippocampal volume and MMSE score. This would be consistent with depression as a causal factor in subsequent cognitive decline. Plausible biological mechanisms include a glucocorticoid cascade or a facilitating effect of depression on amyloid-beta plaque formation. Future studies should examine the relationship between hippocampal volume and specialized memory measures, as well as between depression diagnosis and volume of other brain structures.

Recent years have seen an increase in emphasis on the use of psychological treatments that are supported by empirical data, as advocates have argued these treatments lead to better patient outcomes. We have previously shown that a shift to use of empirically supported treatments in a training clinic led to significant improvement in patient outcomes over four years (Cukrowicz et al., 2005). In the current study, we examined whether average patient outcomes at termination continued to be favorable over the six-year period following the initial shift. We examined data from 549 patients (M age 25.78, SD 10.08; 322 females and 227 males) treated prior to and after the shift to empirically supported treatments, all of whom were rated after termination using the Clinical Global Impression rating scale to track their improvement during treatment. The current study found that improvements in patient outcomes continued over the six-year follow-up period. Patients treated during the follow-up period had superior outcomes when compared to those treated following the initial shift to empirically supported treatments (effect size .28, p 05) and when compared to those treated prior to the shift to empirically supported treatments (effect size 1.83, p .001). Thus, this study points both to the efficacy of empirically supported treatments in clinical practice and to the feasibility of implementing and successfully maintaining EST use in a training clinic setting.

the apolipoprotein E epsilon-4 (APOE [small element of] 4) allele and depression are independently associated with increased risk for cognitive decline (CD). The authors have reported that depressed elders with an APOE [small element of]4 allele had greater CD compared with depressed elders without the allele. Depression affects the hippocampus, and reduced hippocampal volume has been associated with CD. This study sought to examine in depressed patients the relationships between hippocampal volume, the APOE [small element of] 4 allele, and their interaction on CD. Analyses were performed to examine the influence of baseline hippocampal volume, the APOE [small element of] 4 allele, and their interactions on change in cognitive functioning overtime.secondary data analysis using linear regression analyses.clinical Research Center for the Study of Depression in Later Life conducted at Duke University.depressed older patients (N = 61) followed up for 4 years.At baseline, cognitive functioning (assessed by the Mini-Mental State Examination), left and right hippocampal volume (assessed by magnetic resonance imaging), and APOE genotype were obtained. At 4-year follow-up, cognitive functioning was reassessed.the APOE [small element of] 4 allele and left hippocampal volume, but not right hippocampal volume, were independently associated with CD. Importantly, the authors found the APOE [small element of]4 allele to moderate the effects of left hippocampal volume on CD. The APOE [small element of]4 allele seemed to have little effect among those with larger left hippocampal volumes, whereas the allele influenced CD among those with smaller hippocampal volumes.future studies of cognitive impairment and decline should examine both individual and conjoint effects of putative risk factors.

The apolipoprotein (APOE) epsilon4 allele genotype is a risk factor for dementia, but not all people with the APOE epsilon4 allele develop cognitive impairment (CI). Among participants with the APOE epsilon4 allele (N = 664), we identified biological, psychological, and social variables that discriminate between participants who develop CI from those who do not. We then determined if these variables predicted CI in noncarriers (N = 1421). In the sample as a whole we then determined if each of these identified variables moderate the relationship between the APOE epsilon4 allele and CI.We used data from a biracial community-dwelling sample of older adults. Data were collected at four time points over a 10-year period. Cognitive functioning was assessed at each wave, using the Short Portable Mental Status Questionnaire (SPMSQ). APOE genotyping was performed at Wave 3.Among APOE epsilon4 allele carriers, but not noncarriers, variables associated with CI included white race, female gender, low BMI, number of negative life events, and health problems (high blood pressure, heart disease, and stroke). In analyses testing for moderate effects and including the entire sample, significant interactions with APOE epsilon4 allele and predictor variables revealed that white race, low BMI, stroke, heart disease, and negative life events had a greater effect on CI among those with the APOE epsilon4 allele compared to those without the allele.There are biological, psychological, and social variables associated with increased risk for CI among individuals with the APOE epsilon4 allele.

First, to determine if childhood experiences of abuse have an impact on internalizing disorders (e.g., anxiety and depressive disorders) among older adults. Second, we wish to determine if self-esteem plays a role in explaining the relationship between abuse and internalizing disorders.First, we conducted an analysis on a population sample of participants aged 50 years or older (mean age = 67 years; SD = 10.3) assessed at two time points, three years apart (Wave 1, N = 1460; Wave 2, N = 1090). We examined the relationship between reports of childhood abuse (physical, emotional, and sexual) and internalizing disorders. Second, we determined the role self-esteem played in explaining the relationship.We found that childhood experiences of abuse assessed at Wave 1 predicted the number of DSM-IV internalizing disorders occurring three years later. Demonstrating the specificity of self-esteem; we found self-esteem, but not emotional reliance, to moderate the relationship between abuse and internalizing disorders such that childhood abuse had more negative effects on those with low self-esteem compared to those with higher self-esteem. Contrary to prediction, self-esteem did not mediate the relationship between abuse and internalizing disorders.The negative effects of childhood abuse persist for many years, even into older adulthood. However, contrary to the findings in younger adults, self-esteem was not correlated with childhood abuse in older adults. Moreover, childhood abuse only had a negative effect on those who had low self-esteem. It may be through the process of lifespan development that some abused individuals come to separate out the effects of abuse from their self-concept.

Objectives: The apolipoproteinE ɛ4 (APOE ɛ4) allele and a history of depression are each separate risk factors for cognitive decline (CD). However, little research has investigated whether a history of depression influences the relationship between APOE ɛ4 and CD. The present study examined whether depressive symptoms had greater influence on subsequent CD among participants with APOE ɛ4 than those without the allele. Design: Prospective 6-year longitudinal study. Setting: Community in-home interviews. Participants: A biracial sample of community dwelling older adults (N = 1,992) from the Duke Established Populations for Epidemiologic Studies of the Elderly (EPESE). Measurements: Data were drawn from Waves 1 to 3 of the EPESE, which were conducted 6 years apart. Cognitive functioning and depressive symptoms were assessed at both waves, and APOE genotyping was completed during the Wave 3 assessment. Results: Regression analyses revealed that depressive symptoms and the APOE ɛ4 allele independently predicted CD. Importantly, the influence of depressive symptoms on CD was greater for individuals with the APOE ɛ4 allele compared with those without the allele. Conclusion: Depressive symptoms and the APOE ɛ4 allele are independent contributors to CD. Moreover, the influence of depressive symptoms on CD is greater among individuals with the APOE ɛ4 allele. Depression and the APOE ɛ4 allele may act together in disrupting neurological functioning, which may in turn lower an individual's cognitive reserve capacity. Given the efficacious treatments currently available for depression, future research should investigate the extent to which interventions for depression may reduce the risk for subsequent CD.

Background: Most, but not all, past studies have suggested that the APOE genotype is a risk factor for dementia in whites but not African Americans. This paper first describes explanations as to why some studies may have failed to detect the effect of APOE genotype in African American samples. Briefly, studies have been limited by various methodological problems including small sample sizes, dichotomous measures of cognitive functioning (which tend to be less sensitive to change), and racial bias in assessing demented status. Objective: This paper suggests methods for increasing the likelihood that genuine racial differences will be identified when examining genetic risk factors. Further, we test our model of racial differences in the relationship of APOE genotype and cognitive decline (CD) in a large prospective community sample. Methods: Building on the work of Fillenbaum and colleagues [J Am Geriatr Soc 2001;49:1148–1155], we used data from the Duke EPESE study collected in four waves over a 10-year period (n = 2,076) to illustrate methods which may better assess racial differences in the influence of the APOE ε4 allele on CD. We used multilevel models for repeated measures to examine racial differences in participants’ increase in errors on a continuous measure of cognitive functioning as they aged. Results: We found the APOE ε4 allele to predict CD for both African Americans and whites. Having at least one ε4 allele predicted more cognitive errors at wave 1 and a faster rate of decline for both African Americans and whites over time. While African Americans experienced a faster rate of CD than whites, there was no additional increase in CD from being both African American and a carrier of the ε4 allele. Conclusion: The study points to several common methodological issues that arise when examining racial differences in genetic influences on health-related outcomes. Further, the study’s results highlight the importance of including both African Americans and Caucasians in research concerning the contribution of APOE genotype to CD.

Objective: To explore the relationship between headache trajectory across the first year after mild traumatic brain injury (mTBI) and the development of Post Traumatic Stress Disorder (PTSD) one year post-injury. Design: Longitudinal cohort. Setting: Community. Participants: 212 prospectively enrolled individuals diagnosed with mTBI. Interventions: None Main Outcome Measure(s): PTSD was measured by the PTSD ChecklistCivilian Version (PCL-C). Headache trajectories were determined by headache pain rating within 7 days of injury and at 3, 6, and 12 months post-injury. Results: Latent Class Trajectory analysis was used to identify 4 trajectories for headache after mTBI: Resolved (early headache that then went away NZ28), Worsening (limited early headache with increasing over time NZ63), Improving (significant early headache reducing steadily over time NZ23), and Chronic (significant headache across time NZ100). PTSD was found in 13% of the sample and was significantly associated with having a Chronic headache trajectory with 21 of 25 individuals with PTSD falling in this trajectory. Conclusions: The majority of individuals with mTBI had significant issues with headache over time, with most falling into the Worsening and Chronic trajectories, suggesting that early identification and treatment of headache may be important to change trajectory. In addition, having Chronic headache trajectory across the first year was also significantly associated with PTSD at one year after injury. Additional research is needed to determine how headache pain influences development of PTSD and/or how PTSD contributes to chronicity of headaches.

Objectives The atypical depression (AD) subtype has rarely been examined in older patients. However, younger AD patients have been characterized as having more severe and chronic symptoms of depression compared with non-AD patients. Design Secondary data analysis by using analyses of variance and Growth Curve Modeling. Setting Clinical Research Center for the study of depression in later life. Participants Depressed older patients (N = 248) followed over 2 years. Method In a longitudinal study, we examined depression severity and chronicity in patients with major depression with some features of AD, specifically rejection sensitivity and reversed-vegetative symptoms (e.g., hyperphagia and hypersomnia), or leaden paralysis, and compared them to non-AD patients. The Diagnostic Interview Schedule (DIS) was used to assess depressive symptoms and history. Depression severity and chronicity were assessed every 3 months by using the Montgomery Asberg Depression Rating Scale. Results The AD symptom group reported more DIS depressive symptoms, more thoughts about wanting to die, earlier age of onset, poorer social support, and double the number of lifetime episodes than non-AD patients. Growth curve analyses revealed that, compared with non-AD patients, the AD symptom group had more residual symptoms of depression during the first year of follow-up but not during the second year. Conclusion Characteristics of older patients with features of AD are similar to younger patients. Assessment of atypical symptoms, in particular, rejection sensitivity and reversed-vegetative symptoms, is essential and should be considered in treatment plans.

The ApolipoproteinE epsilon4 (APOE epsilon4) allele influences cognitive decline (CD) in some but not in all individuals. The purpose of this study was to investigate whether problems meeting basic needs (BN) (e.g., having enough money to meet needs, having enough money for emergencies, having adequate housing, and having enough heat) influences the relationship between the APOE epsilon4 allele and CD. We predicted that problems meeting BN would have a greater influence on CD among those with the APOE epsilon4 allele than those without the allele.Participants consisted of community-dwelling older adults from the Duke Established Populations for Epidemiologic Studies of the Elderly (EPESE). Data were drawn from Waves 1 and 2, which were 3 years apart. Cognitive functioning was assessed at both waves so that change in cognitive status was examined over time, and cognitive status was controlled at baseline. Genotyping, however, was not obtained until Wave 3.The APOE epsilon4 allele and problems meeting BN independently predicted CD. Importantly, the influence of BN on CD was greater for individuals with the APOE epsilon4 allele compared to those without the allele. Other indicators of socioeconomic status (e.g., education, income) did not interact with the APOE epsilon4 allele in predicting CD.There is a synergistic effect of perceived problems meeting BN and the APOE epsilon4 allele on jointly influencing cognitive functioning. Although genetic risk factors are not easily modifiable, resource deprivation may be more amenable to interventions, which may reduce risk for CD.