Jefferson Hospital for Neuroscience

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Childhood socioeconomic status (SES) predicts executive function (EF), but fundamental aspects of this relation remain unknown: the developmental course of the SES disparity, its continued sensitivity to SES changes during that course, and the features of childhood experience responsible for the SES-EF relation. Regarding course, early disparities would be expected to grow during development if caused by accumulating stressors at a given constant level of SES. Alternatively, they would narrow if schooling partly compensates for the effects of earlier deprivation, allowing lower-SES children to 'catch up'. The potential for later childhood SES change to affect EF is also unknown. Regarding mediating factors, previous analyses produced mixed answers, possibly due to correlation amongst candidate mediators. We address these issues with measures of SES, working memory and planning, along with multiple candidate mediators, from the NICHD Study of Early Childcare (n = 1009). Early family income-to-needs and maternal education predicted planning by first grade, and income-to-needs predicted working memory performance at 54 months. Effects of early SES remained consistent through middle childhood, indicating that the relation between early indicators of SES and EF emerges in childhood and persists without narrowing or widening across early and middle childhood. Changes in family income-to-needs were associated with significant changes in planning and trend-level changes in working memory. Mediation analyses supported the role of early childhood home characteristics in explaining the association between SES and EF, while early childhood maternal sensitivity was specifically implicated in the association between maternal education and planning. Early emerging and persistent SES-related differences in EF, partially explained by characteristics of the home and family environment, are thus a potential source of socioeconomic disparities in achievement and health across development.

Intracranial aneurysms (IAs) linger as a potentially devastating clinical problem. Despite intense investigation, our understanding of the mechanisms leading to aneurysm development, progression and rupture remain incompletely defined. An accumulating body of evidence implicates inflammation as a critical contributor to aneurysm pathogenesis. Intracranial aneurysm formation and progression appear to result from endothelial dysfunction, a mounting inflammatory response, and vascular smooth muscle cell phenotypic modulation producing a pro-inflammatory phenotype. A later final common pathway appears to involve apoptosis of cellular constituents of the vessel wall. These changes result in degradation of the integrity of the vascular wall leading to aneurysmal dilation, progression and eventual rupture in certain aneurysms. Various aspects of the inflammatory response have been investigated as contributors to IA pathogenesis including leukocytes, complement, immunoglobulins, cytokines, and other humoral mediators. Furthermore, gene expression profiling of IA compared with control arteries has prominently featured differential expression of genes involved with immune response/inflammation. Preliminary data suggest that therapies targeting the inflammatory response may have efficacy in the future treatment of IA. Further investigation, however, is necessary to elucidate the precise role of inflammation in IA pathogenesis, which can be exploited to improve the prognosis of patients harboring IA.

BACKGROUND AND PURPOSE: Self-expanding stents are increasingly used for treatment of complex intracranial aneurysms. We assess the safety and the efficacy of intracranial stenting and determine predictors of treatment outcomes. METHODS: A total of 508 patients with 552 aneurysms were treated with Neuroform and Enterprise stents between 2006 and 2011 at our institution. A multivariate analysis was conducted to identify predictors of complications, recanalization, and outcome. RESULTS: Of 508 patients, 461 (91%) were treated electively and 47 (9%) in the setting of subarachnoid hemorrhage. Complications occurred in 6.8% of patients. In multivariate analysis, subarachnoid hemorrhage, delivery of coils before stent placement, and carotid terminus/middle cerebral artery aneurysm locations were independent predictors of procedural complications. Angiographic follow-up was available for 87% of patients at a mean of 26 months. The rates of recanalization and retreatment were, respectively, 12% and 6.4%. Older age, previously coiled aneurysms, larger aneurysms, incompletely occluded aneurysms, Neuroform stent, and aneurysm location were predictors of recanalization. Favorable outcomes were seen in 99% of elective patients and 51% of subarachnoid hemorrhage patients. Patient age, ruptured aneurysms, and procedural complications were predictors of outcome. CONCLUSIONS: Stent-assisted coiling of intracranial aneurysms is safe, effective, and provides durable aneurysm closure. Higher complication rates and worse outcomes are associated with treatment of ruptured aneurysms. Stent delivery before coil deployment reduces the risk of procedural complications. Staging the procedure may not improve procedural safety. Closed-cell stents are associated with significantly lower recanalization rates.

Importance: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed. Objective: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma. Design, Setting, and Participants: This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021. Interventions: The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies. Main Outcomes and Measures: The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials. Results: A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03). Conclusions and Relevance: In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone. Trial Registration: ClinicalTrials.gov Identifier: NCT00045968.

For approximately 80 years following Alzheimer's description of the disease that bears his name, a gulf divided researchers who believed that extracellular deposits of the amyloid beta (Abeta) peptide were pathogenic from those who believed that the deposits were secondary detritus. Since 1990, the discoveries of missense mutations in the Abeta peptide precursor (APP) and the APP-cleaving enzyme presenilin 1 (PS1) have enabled much progress in understanding the molecular, cellular, and tissue pathology of the aggregates that accumulate in the interstices of the brains of patients with autosomal dominant familial Alzheimer disease (AD). Clarification of the molecular basis of common forms of AD has been more elusive. The central questions in common AD focus on whether cerebral and cerebrovascular Abeta accumulation is (a) a final neurotoxic pathway, common to all forms of AD; (b) a toxic by-product of an independent primary metabolic lesion that, by itself, is also neurotoxic; or (c) an inert by-product of an independent primary neurotoxic reaction. Antiamyloid medications are entering clinical trials so that researchers can evaluate whether abolition of cerebral amyloidosis can mitigate, treat, or prevent the dementia associated with common forms of AD. Successful development of antiamyloid medications is critical for elucidating the role of Abeta in common AD.

OBJECTIVE: The long-term durability of the endovascular occlusion of cerebral aneurysms is one of the major factors limiting the more widespread use of this technique. Long-term occlusion of wide-necked aneurysms has improved with new assistive devices that seem to improve aneurysm occlusion while protecting the parent vessel. We report the use of a new intracranial stent--the Neuroform microstent--in the treatment of patients with wide-necked cerebral aneurysms. METHODS: Patients identified as harboring wide-necked intracranial aneurysms were evaluated for stent-assisted coiling. After appropriate anticoagulation was performed, depending on whether the aneurysm was ruptured or unruptured, the Neuroform stent was delivered across the neck of the aneurysm and deployed with a coil pusher. After stent placement, standard coil occlusion of the aneurysm was achieved in the majority of cases. RESULTS: Fifty-six patients were identified as having wide-necked intracranial aneurysms suitable for stent-assisted coiling. A total of 49 aneurysms in 48 patients were treated with this procedure. In eight cases, stent deployment failed. Forty-one of the aneurysms were initially stented, followed by coil placement. Six aneurysms were stented only, and one aneurysm was initially coiled, followed by stent placement. There were five deaths (8.9%), one of which occurred secondary to a stroke after the procedure (1.8%). Four patients (7%) experienced thromboembolic events, three of which were considered to have been secondary to the procedure (5.3%). In addition, there were two femoral pseudoaneurysms. The overall complication rate was 10.7%. Five patients were available for follow-up angiographic evaluation, and their cases are discussed. CONCLUSION: Intracranial stenting may overcome important technical limitations in current endovascular therapy by improving the occlusion of wide-necked aneurysms while protecting the parent vessel.

Migraine is a common disabling primary headache disorder that affects an estimated 36 million Americans. Migraine headaches often occur over many years or over an individual's lifetime. By definition, episodic migraine is characterized by headaches that occur on fewer than 15 days per month. According to the recent International Classification of Headache Disorders (third revision) beta diagnostic criteria, chronic migraine is defined as "headaches on at least 15 days per month for at least 3 months, with the features of migraine on at least 8 days per month." However, diagnostic criteria distinguishing episodic from chronic migraine continue to evolve. Persons with episodic migraine can remit, not change, or progress to high-frequency episodic or chronic migraine over time. Chronic migraine is associated with a substantially greater personal and societal burden, more frequent comorbidities, and possibly with persistent and progressive brain abnormalities. Many patients are poorly responsive to, or noncompliant with, conventional preventive therapies. The primary goals of migraine treatment include relieving pain, restoring function, and reducing headache frequency; an additional goal may be preventing progression to chronic migraine. Although all migraineurs require abortive treatment, and all patients with chronic migraine require preventive treatment, there are no definitive guidelines delineating which persons with episodic migraine would benefit from preventive therapy. Five US Food and Drug Association strategies are approved for preventing episodic migraine, but only injections with onabotulinumtoxinA are approved for preventing chronic migraine. Identifying persons who require migraine prophylaxis and selecting and initiating the most appropriate treatment strategy may prevent progression from episodic to chronic migraine and alleviate the pain and suffering associated with frequent migraine.

1. Early Vision. 2. From Local To Global Image Representation. 3. The Problem Of Visual Recognition. 4. Object Recognition. 5. Face Recognition. 6. Word Recognition. 7. Visual Attention. 8. Hemispatial Neglect. 9. Mental Imagery. 10. Visual Awareness.

Responsible for the majority of excitatory activity in the central nervous system (CNS), glutamate interacts with a range of specific receptor and transporter systems to establish a functional synapse. Excessive stimulation of glutamate receptors causes excitotoxicity, a phenomenon implicated in both acute and chronic neurodegenerative diseases [e.g., ischemia, Huntington's disease, and amyotrophic lateral sclerosis (ALS)]. In physiology, excitotoxicity is prevented by rapid binding and clearance of synaptic released glutamate by high-affinity, Na(+)-dependent glutamate transporters and amplified by defects to the glutamate transporter and receptor systems. ALS pathogenetic mechanisms are not completely understood and characterized, but excitotoxicity has been regarded as one firm mechanism implicated in the disease because of data obtained from ALS patients and animal and cellular models as well as inferred by the documented efficacy of riluzole, a generic antiglutamatergic drug, has in patients. In this article, we critically review the several lines of evidence supporting a role for glutamate-mediated excitotoxicity in the death of motor neurons occurring in ALS, putting a particular emphasis on the impairment of the glutamate-transport system.

BACKGROUND AND PURPOSE: Flow diversion has emerged as an important tool for the management of intracranial aneurysms. The purpose of this study was to compare flow diversion and traditional embolization strategies in terms of safety, efficacy, and clinical outcomes in patients with unruptured, large saccular aneurysms (≥10 mm). METHODS: Forty patients treated with the Pipeline Embolization Device (PED) were matched in a 1:3 fashion with 120 patients treated with coiling based on patient age and aneurysm size. Fusiform and anterior communicating artery aneurysms were eliminated from the analysis. Procedural complications, angiographic results, and clinical outcomes were analyzed and compared. RESULTS: There were no differences between the 2 groups in terms of patient age, sex, aneurysm size, and aneurysm location. The rate of procedure-related complications did not differ between the PED (7.5%) and the coil group (7.5%; P=1). At the latest follow-up, a significantly higher proportion of aneurysms treated with PED (86%) achieved complete obliteration compared with coiled aneurysms (41%; P<0.001). In multivariable analysis, coiling was an independent predictor of nonocclusion. Retreatment was necessary in fewer patients in the PED group (2.8%) than the coil group (37%; P<0.001). A similar proportion of patients attained a favorable outcome (modified Rankin Scale, 0-2) in the PED group (92%) and in the coil group (94%; P=0.8). CONCLUSIONS: The PED provides higher aneurysm occlusion rates than coiling, with no additional morbidity and similar clinical outcomes. These findings suggest that the PED might be a preferred treatment option for large unruptured saccular aneurysms.

Given the range of disorders that produce headache, a systematic approach to classification and diagnosis is an essential prelude to clinical management. For the last 15 years, the diagnostic criteria of the International Headache Society (IHS) have been the accepted standard. The second edition of The International Classification of Headache Disorders (January 2004) reflects our improved understanding of some disorders and the identification of new disorders. Neurologists who treat headache should become familiar with the revised criteria. Like its predecessor, the second edition of the IHS classification separates headache into primary and secondary disorders. The four categories of primary headaches include migraine, tension-type headache, cluster headache and other trigeminal autonomic cephalalgias, and other primary headaches. There are eight categories of secondary headache. Important changes in the second edition include a restructuring of these criteria for migraine, a new subclassification of tension-type headache, introduction of the concept of trigeminal autonomic cephalalgias, and addition of previously unclassified primary headaches. Several disorders were eliminated or reclassified. In this article, the authors present an overview of the revised IHS classification, highlighting the primary headache disorders and their diagnostic criteria. They conclude by presenting an approach to headache diagnosis based upon these criteria.

Sensory integration is one of the most highly utilized interventions in autism, however, a lack of consensus exists regarding its evidence base. An increasing number of studies are investigating the effectiveness of this approach. This study used the Council for Exceptional Children (CEC) Standards for Evidence-based Practices in Special Education to evaluate the effectiveness research from 2006 to 2017 on Ayres Sensory Integration (ASI) intervention for children with autism. A systematic review was conducted in three stages. Stage 1 involved an extensive database search for relevant studies using search terms related to sensory integration and autism, interventions suggesting a sensory integration approach, and high-quality study designs. Searches yielded 19 studies that were evaluated in Stage 2. Six of these met inclusion criteria of being peer-reviewed, written in English, description of intervention this is consistent with ASI intervention, and comparison group design or single subject method employed. Prior to analysis using CEC standards, three articles were excluded because intervention details were not consistent with the core principles of ASI, or because of major methodological flaws. In Stage 3, the remaining three studies were rated using the CEC quality indicators and standards for an evidence-based practice. Two randomized controlled trials respectively met 100% and 85% of the CEC criteria items. One additional study met more than 50% of the criteria. Based on CEC criteria, ASI can be considered an evidence-based practice for children with autism ages 4-12 years old. Autism Research 2019, 12: 6-19. © 2018 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: Ayres Sensory Integration intervention is one of the most frequently requested and highly utilized interventions in autism. This intervention has specific requirements for therapist qualifications and the process of therapy. This systematic review of studies providing Ayres Sensory Integration therapy to children with autism indicates that it is an evidence-based practice according to the criteria of the Council for Exceptional Children.

Alzheimer's disease (AD) is the most commonly diagnosed form of dementia in the elderly. Predominantly this disease is sporadic in nature with only a small percentage of patients exhibiting a familial trait. Early-onset AD may be explained by single gene defects; however, most AD cases are late onset (> 65 years) and, although there is no known definite cause for this form of the disease, there are several known risk factors. Of these, the epsilon4 allele of the apolipoprotein E (apoE) gene (APOE) is a major risk factor. The epsilon4 allele of APOE is one of three (epsilon2 epsilon3 and epsilon4) common alleles generated by cysteine/arginine substitutions at two polymorphic sites. The possession of the epsilon 4 allele is recognized as the most common identifiable genetic risk factor for late-onset AD across most populations. Unlike the pathogenic mutations in the amyloid precursor or those in the presenilins, APOE epsilon4 alleles increase the risk for AD but do not guarantee disease, even when present in homozygosity. In addition to the cysteine/arginine polymorphisms at the epsilon2/epsilon3/epsilon4 locus, polymorphisms within the proximal promoter of the APOE gene may lead to increased apoE levels by altering transcription of the APOE gene. Here we review the genetic and biochemical evidence supporting the hypothesis that regulation of apoE protein levels may contribute to the risk of AD, distinct from the well known polymorphisms at the epsilon2/epsilon3/epsilon4 locus.

Aberrant hexanucleotide repeat expansions in C9orf72 are the most common genetic change underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). RNA transcripts containing these expansions undergo repeat-associated non-ATG translation (RAN-T) to form five dipeptide repeat proteins (DPRs). DPRs are found as aggregates throughout the CNS of C9orf72-ALS/FTD patients, and some cause degeneration when expressed in vitro in neuronal cultures and in vivo in animal models. The spread of characteristic disease-related proteins drives the progression of pathology in many neurodegenerative diseases. While DPR toxic mechanisms continue to be investigated, the potential for DPRs to spread has yet to be determined. Using different experimental cell culture platforms, including spinal motor neurons derived from induced pluripotent stem cells from C9orf72-ALS patients, we found evidence for cell-to-cell spreading of DPRs via exosome-dependent and exosome-independent pathways, which may be relevant to disease.

OBJECTIVE: Laser interstitial thermal therapy (LITT) for mesial temporal lobe epilepsy (mTLE) has reported seizure freedom rates between 36% and 78% with at least 1 year of follow-up. Unfortunately, the lack of robust methods capable of incorporating the inherent variability of patient anatomy, the variability of the ablated volumes, and clinical outcomes have limited three-dimensional quantitative analysis of surgical targeting and its impact on seizure outcomes. We therefore aimed to leverage a novel image-based methodology for normalizing surgical therapies across a large multicenter cohort to quantify the effects of surgical targeting on seizure outcomes in LITT for mTLE. METHODS: This multicenter, retrospective cohort study included 234 patients from 11 centers who underwent LITT for mTLE. To investigate therapy location, all ablation cavities were manually traced on postoperative magnetic resonance imaging (MRI), which were subsequently nonlinearly normalized to a common atlas space. The association of clinical variables and ablation location to seizure outcome was calculated using multivariate regression and Bayesian models, respectively. RESULTS: Ablations including more anterior, medial, and inferior temporal lobe structures, which involved greater amygdalar volume, were more likely to be associated with Engel class I outcomes. At both 1 and 2 years after LITT, 58.0% achieved Engel I outcomes. A history of bilateral tonic-clonic seizures decreased chances of Engel I outcome. Radiographic hippocampal sclerosis was not associated with seizure outcome. SIGNIFICANCE: LITT is a viable treatment for mTLE in patients who have been properly evaluated at a comprehensive epilepsy center. Consideration of surgical factors is imperative to the complete assessment of LITT. Based on our model, ablations must prioritize the amygdala and also include the hippocampal head, parahippocampal gyrus, and rhinal cortices to maximize chances of seizure freedom. Extending the ablation posteriorly has diminishing returns. Further work is necessary to refine this analysis and define the minimal zone of ablation necessary for seizure control.

Recent studies suggest that Cu/Zn superoxide dismutase (SOD1) could be pathogenic in both familial and sporadic amyotrophic lateral sclerosis (ALS) through either inheritable or nonheritable modifications. The presence of a misfolded WT SOD1 in patients with sporadic ALS, along with the recently reported evidence that reducing SOD1 levels in astrocytes derived from sporadic patients inhibits astrocyte-mediated toxicity on motor neurons, suggest that WT SOD1 may acquire toxic properties similar to familial ALS-linked mutant SOD1, perhaps through posttranslational modifications. Using patients' lymphoblasts, we show here that indeed WT SOD1 is modified posttranslationally in sporadic ALS and is iper-oxidized (i.e., above baseline oxidation levels) in a subset of patients with bulbar onset. Derivatization analysis of oxidized carbonyl compounds performed on immunoprecipitated SOD1 identified an iper-oxidized SOD1 that recapitulates mutant SOD1-like properties and damages mitochondria by forming a toxic complex with mitochondrial Bcl-2. This study conclusively demonstrates the existence of an iper-oxidized SOD1 with toxic properties in patient-derived cells and identifies a common SOD1-dependent toxicity between mutant SOD1-linked familial ALS and a subset of sporadic ALS, providing an opportunity to develop biomarkers to subclassify ALS and devise SOD1-based therapies that go beyond the small group of patients with mutant SOD1.

The evolution of imaging techniques and their increased use in clinical practice have led to a higher detection rate of unruptured intracranial aneurysms. The diagnosis of an unruptured intracranial aneurysm is a source of significant stress to the patient because of the concerns for aneurysmal rupture, which is associated with substantial rates of morbidity and mortality. Therefore, it is important that decisions regarding optimum management are made based on the comparison of the risk of aneurysmal rupture with the risk associated with intervention. This review provides a comprehensive overview of the epidemiology, pathophysiology, natural history, clinical presentation, diagnosis, and management options for unruptured intracranial aneurysms based on the current evidence in the literature. Furthermore, the authors discuss the genetic abnormalities associated with intracranial aneurysm and current guidelines for screening in patients with a family history of intracranial aneurysms. Since there is significant controversy in the optimum management of small unruptured intracranial aneurysms, we provided a systematic approach to their management based on patient and aneurysm characteristics as well as the risks and benefits of intervention.

BACKGROUND: M1 and M2 cells are two major subsets of human macrophages that exert opposite effects on the inflammatory response. This study aims to investigate the role of macrophage M1/M2 imbalance and mast cells in the progression of human cerebral aneurysms to rupture. METHODS: Ten patients with cerebral aneurysms (five ruptured and five unruptured) underwent microsurgical clipping. During the procedure, a segment of the aneurysm dome was resected and immunostained with monoclonal antibodies for M1 cells (anti-HLA DR), M2 cells (anti-CD 163), and mast cells (anti-tryptase clone AA). A segment of the superficial temporal artery (STA) was also removed and immunostained with monoclonal antibodies for M1, M2, and mast cells. RESULTS: All ten aneurysm tissues stained positive for M1, M2, and mast cells. M1 and M2 cells were present in equal proportions in unruptured aneurysms. This contrasted with a marked predominance of M1 over M2 cells in ruptured aneurysms (p = 0.045). Mast cells were also prominently upregulated in ruptured aneurysms (p = 0.001). Few M1 and M2 cells were present in STA samples. CONCLUSIONS: M1/M2 macrophages and mast cells are found in human cerebral aneurysms; however, M1 and mast cell expression seems to markedly increase in ruptured aneurysms. These findings suggest that macrophage M1/M2 imbalance and upregulation of mast cells may have a role in the progression of cerebral aneurysms to rupture.

CONTEXT: Age-related macular degeneration is a prevalent disease of aging that may cause irreversible vision loss, disability, and depression. The latter is rarely recognized or treated in ophthalmologic settings. OBJECTIVE: To determine whether problem-solving treatment can prevent depressive disorders in patients with recent vision loss. DESIGN: Randomized, controlled trial. SETTING: Outpatient ophthalmology offices in Philadelphia, Pennsylvania. PATIENTS: Two hundred six patients aged 65 years or older with recent diagnoses of neovascular age-related macular degeneration in one eye and pre-existing age-related macular degeneration in the fellow eye. INTERVENTION: Patients were randomly assigned to problem-solving treatment (n = 105) or usual care (n = 101). Problem-solving treatment therapists delivered 6 sessions during 8 weeks in subjects' homes. MAIN OUTCOME MEASURES: Outcomes were assessed at 2 months for short-term effects and 6 months for maintenance effects. These included DSM-IV-defined diagnoses of depressive disorders, National Eye Institute Vision Function Questionnaire-17 scores, and rates of relinquishing valued activities. RESULTS: The 2-month incidence rate of depressive disorders in problem-solving-treated subjects was significantly lower than controls (11.6% vs 23.2%, respectively; odds ratio, 0.39; 95% confidence interval, 0.17-0.92; P = .03). Problem-solving treatment also reduced the odds of relinquishing a valued activity (odds ratio, 0.48; 95% confidence interval, 0.25-0.96; P = .04). This effect mediated the relationship between treatment group and depression. By 6 months, most earlier observed benefits had diminished, though problem-solving treatment subjects were less likely to suffer persistent depression (chi2(1,3) = 8.46; P = .04). CONCLUSIONS: Problem-solving treatment prevented depressive disorders and loss of valued activities in patients with age-related macular degeneration as a short-term treatment, but these benefits were not maintained over time. Booster or rescue treatments may be necessary to sustain problem-solving treatment's preventative effect. This study adds important new information to the emerging field of enhanced-care models to prevent or treat depression in older persons. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00042211.