Background: Progressive accumulation of aggregates distributing along anatomical pathways are the hall marks of common non-infectious neurodegenerative diseases like Alzheimer’s, Parkinson’s, frontotemporal dementia and Huntington’s. Recent reports demonstrated neuron to neuron transmission of the known pathogens of above diseases such as tau, a-synuclein and huntingtin and superoxide dismutase-1, suggesting mechanisms similar to prion transfer. Aß aggregates spreads close to the site of injected brain extracts from Alzheimer’s disease patients into the brain of amyloid precursor protein (APP) transgenic mice. Aß reduces the spine number and plasticity of neighboring cells and neuronal dysfunction induced by Aß can progress trans-synaptically. However it has not been demonstrated that neuron to neuron transmission of Aß actually takes place. Speculation of Prion like transmission have been put forward but its existence has until now remained elusive. Methods:Here we demonstrate transmission of Aß between neuronal cells using a donor and acceptor cells co-culturing and microinjection method. We show that exogenous Aß42 oligomers after uptake by differentiated human neuronal cell-line are subsequently transferred to co-cultured neuronal cells. Transfer from a single, microinjected hippocampal rat neuron to connected neurons was also shown. Results: The data presented here shows that oligomeric Aß is transmitted from neuron to neuron through neuritic connections which subsequently but slowly affects cells cytotoxicity. Oligomer spreading is restricted to neighboring rat neuron when injected. Transmission is very specific and seems to involve endosomal-lysosomal pathway, and is not inhibited by blockers of suggested Aß binding receptors. Conclusions: The finding of neuron to neuron transfer of Aß sheds important light on the propagation of Alzheimer’s disease through anatomical connections, suggesting similarities with other common neurodegenerative diseases, also dependent on cell nonautonomous mechanisms. This opens new avenues for the search for novel treatment.

No head-to-head clinical trial has compared the efficacy of adalimumab versus etanercept as first-line therapy for patients with psoriatic arthritis (PsA). To bridge this gap, we implemented a matching-adjusted indirect comparison of adalimumab versus etanercept for PsA. Using methodology developed by Signorovitch, patient-level data from the adalimumab randomized controlled trial (RCT) ADEPT were reweighted to match baseline characteristics from the pivotal published etanercept RCT. ADEPT patients were reweighted by their odds of enrollment in the etanercept trial, estimated using logistic regression model. Matched characteristics included demographics, baseline clinical measures, and concomitant treatment. After matching, biologic treatment arms were compared based on difference from placebo in percent achieving ≥20%, ≥50%, or ≥70% improvement in ACR criteria (ACR20/50/70), percent meeting PsA Response Criteria (PsARC), mean change in Health Assessment Questionnaire (HAQ), percent with ≥50%, ≥75%, or ≥90% improvement in PASI (PASI50/75/90), and change from baseline in modified total Sharp score (mTSS). Statistical significance was assessed using weighted Student's t-tests. After reweighting, baseline characteristics were exactly matched across trials. Compared with etanercept-treated patients, adalimumab-treated patients had greater placebo-adjusted rates of ACR70 (23.9% vs. 7.9%), PASI50 (60.5% vs. 29.2%), PASI75 (55.0% vs. 19.5%), and PASI90 (40.2% vs. 2.8%) at Week 24 (all p<0.05). Adalimumab-treated patients also had greater change from baseline vs. placebo in mTSS (1.77 vs. 0.56, p=0.080) at Week 24 and greater rate of ACR70 (20.6% vs. 9.7%, p=0.055) at Week 12. No significant differences were found for ACR20, ACR50, PsARC, and HAQ change (all p>0.1). Matching-adjusted indirect comparison of adalimumab vs. etanercept in PsA finds that adalimumab treatment is associated with greater probability of ACR70, PASI50, PASI75, and PASI90 at Week 24.

Recent research on biomarkers for Alzheimer's disease (AD) suggests possibilities for earlier diagnosis and treatment. Existing treatments, however, focus on symptomatic relief, and controlled clinical trials have shown little effect on disease progression and time to institutionalization. This study assesses effects of treatment timing on risk of institutionalization of AD patients in a real-world setting. Retrospective analysis of administrative claims data for New Jersey Medicaid patients (1997-2009). Patients were included if they had ≥2 claims with AD diagnosis, or ≥1 claim and a prescription for AD treatment (donepezil, galantamine, memantine, rivastigmine, or tacrine); N=5,790. The index date was defined as the earliest claim with any dementia/memory loss diagnosis (ICD-9-CM: 290, 291.2, 292.82, 294, 331, 780.93), possibly preceding AD diagnosis. Institutionalization was defined as ≥90-day stay in a long-term care facility. The effect of treatment on institutionalization risk was estimated at the patient-quarter level using logistic regression with repeated measures, controlling for a quadratic time-trend and baseline characteristics. The model was used to predict the conditional probability (hazard rate) of institutionalization by prior treatment and quarter following index diagnosis. In turn, predicted hazard curves were constructed for different treatment scenarios. Median interval to treatment was 7 quarters (21 months) from index date diagnosis. Treatment in prior quarters reduced institutionalization risk [OR 0.88, CI 0.78-0.99]. Older age on index and AD diagnosis in prior quarters increased institutionalization risk. The predicted hazard curves imply that initiating treatment at the earliest observed onset of memory-loss symptoms could delay institutionalization by ∼4 months, compared with median observed initiation. Treatment in earlier periods is associated with a small statistically significant delay in time to institutionalization among AD patients, possibly due to reduction in symptom burden. These findings may be especially relevant in light of new criteria facilitating earlier diagnosis of AD.

To compare real-world healthcare costs after initiation of second-line antidepressant treatment with duloxetine vs. generic selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder (MDD). Study sample was selected from a de-identified U.S. privately-insured claims database (2005-2009). Selection criteria: age 18-64 years, ≥1 MDD diagnosis (ICD-9-CM: 296.2, 296.3) in an inpatient setting or ≥2 MDD diagnoses in emergency room/outpatient settings, initiation of an antidepressant treatment after a 3-month washout, initiation of a second-line treatment with duloxetine or generic SSRI (defined as the index date) no later than 90 days after the end of first-line treatment, continuous coverage eligibility from 6 months before the index date (baseline period) to 12 months after the index date (study period). Using optimal matching on propensity scores and baseline costs, 838 patients initiating second-line duloxetine were matched to 838 patients initiating second-line generic SSRI. McNemar tests were used to compare proportions. Bias-corrected bootstrapping was used to compare healthcare costs (reimbursement to providers for medical services and prescription drugs) inflated to 2009 dollars. Before matching, second-line duloxetine compared with generic SSRI users were older, more likely to be female, had a higher rate of chronic pain, and had higher baseline prescription drug costs and $2,967 higher study period healthcare costs. After matching, there were no notable differences in baseline characteristics and costs. After matching, neither study period healthcare costs ($11,342 vs. $10,328, p=.2316) nor medical costs ($8,377 vs. $8,051 p=.7063) were significantly different between second-line duloxetine and generic SSRI users. Prescription drug costs were significantly higher for second-line duloxetine users ($2,965 vs. $2,277, p<.0001), largely due to differences in mental health-related drug costs ($1,605 vs. $1,008, p<.0001). Controlling for patient differences, this study found that second-line duloxetine users had similar medical costs and higher drug costs compared with second-line generic SSRI users.

The study compared the demographic and comorbidity profile and direct healthcare costs of Medicaid patients with post herpetic neuralgia (PHN) treated with lidocaine patch 5% (lidocaine) with that of patients not treated with the patch. The comparison was also conducted in the subset of patients treated in long-term care (LTC) setting. Patients, age ≥18 years, with PHN diagnosis or PHN-likely patients with herpes zoster diagnosis and ≥30 days of PHN-related treatment were identified from Medicaid claims data from Florida, Iowa, Missouri, and New Jersey during 1999-2007. Patients had continuous eligibility 6 months before (baseline) and 12 months after (study period) the PHN index date. Patients with at least one lidocaine claim during the study period comprised the lidocaine group and those without a lidocaine claim were assigned to the other group. Lidocaine patients (n=872) were matched to 872 other group patients on diagnosis type (PHN or PHN-likely). Baseline characteristics, study period direct costs, calculated as reimbursements to third-party payers for medical services and prescription drugs, were compared between the two groups using univariate analysis. PHN patients in the lidocaine group were older (64.5 vs. 62.2 years, P=0.002) and had more comorbidities (e.g., back/neck pain, osteoarthritis) compared with the other group. Lidocaine patients were more likely to receive gabapentin, pregabalin, and analgesic medications during the study period. While average drug costs per patient ($7,658 vs. $6,198, P<0.001) were higher in the lidocaine group compared with the other group, there were no significant differences in the overall direct costs ($20,175 vs. $19,124, P=0.372). Similarly, among LTC patients there were no significant differences in direct costs ($52,244 vs. $52,473, P= 0.981). Despite higher rates of comorbidities and drug costs, lidocaine patients had similar study period healthcare costs as the other group, suggesting an offsetting effect of lower medical costs in the lidocaine group. The study compared the demographic and comorbidity profile and direct healthcare costs of Medicaid patients with post herpetic neuralgia (PHN) treated with lidocaine patch 5% (lidocaine) with that of patients not treated with the patch. The comparison was also conducted in the subset of patients treated in long-term care (LTC) setting. Patients, age ≥18 years, with PHN diagnosis or PHN-likely patients with herpes zoster diagnosis and ≥30 days of PHN-related treatment were identified from Medicaid claims data from Florida, Iowa, Missouri, and New Jersey during 1999-2007. Patients had continuous eligibility 6 months before (baseline) and 12 months after (study period) the PHN index date. Patients with at least one lidocaine claim during the study period comprised the lidocaine group and those without a lidocaine claim were assigned to the other group. Lidocaine patients (n=872) were matched to 872 other group patients on diagnosis type (PHN or PHN-likely). Baseline characteristics, study period direct costs, calculated as reimbursements to third-party payers for medical services and prescription drugs, were compared between the two groups using univariate analysis. PHN patients in the lidocaine group were older (64.5 vs. 62.2 years, P=0.002) and had more comorbidities (e.g., back/neck pain, osteoarthritis) compared with the other group. Lidocaine patients were more likely to receive gabapentin, pregabalin, and analgesic medications during the study period. While average drug costs per patient ($7,658 vs. $6,198, P<0.001) were higher in the lidocaine group compared with the other group, there were no significant differences in the overall direct costs ($20,175 vs. $19,124, P=0.372). Similarly, among LTC patients there were no significant differences in direct costs ($52,244 vs. $52,473, P= 0.981). Despite higher rates of comorbidities and drug costs, lidocaine patients had similar study period healthcare costs as the other group, suggesting an offsetting effect of lower medical costs in the lidocaine group.

Many studies suggest that surgery for low back pain (LBP) is excessive, expensive, and often ineffective. We examine the interaction among LBP patients, of demographics, LBP diagnosis categories, co-morbidities, noninvasive therapy use, and medication use to identify diagnostic-treatment pathways that may modify likelihood of LBP surgery using CHAID (Chi-square automatic interaction detector analysis.) The 211,551 patients, ages 18-64 years, with >1 LBP diagnosis, as specified by HEDIS, between 2002 and 2006 were identified from a large administrative claims data. Patients had continuous eligibility >12 months after their index LBP diagnosis (study period) and >6 months before their index diagnosis (baseline period) and no other LBP diagnosis during the baseline period. Exploratory CHAID and logistic analyses were used to identify subgroups of the population most likely to undergo surgery. There were 4,331 patients (2.05%) who had back surgery during the study period (median: 90 days after LBP diagnosis). The likelihood of surgery increased with: age; in men; with severe LBP diagnoses such as spinal stenosis, herniated disc; chronic duration (>3 months); and prior depression. Other co-morbidities (Charlson Index, osteoporosis, asthma) decreased the likelihood of surgery. Use of opiates and corticosteroids appeared associated with increased risk and noninvasive therapies, such as chiropractic and exercise therapies, NSAIDs, and some antidepressants with lower risk. LBP chronicity and diagnostic severity, with combinations of some treatments such as opioids, corticosteroids, chiropractic therapy, NSAIDs, and antidepressants were associated with variations in subpopulation surgery risk rates from >1% to 24%. In summary, surgery risk varies with more conservative, noninvasive therapy and medication combinations, but causality cannot be inferred. Studies to model treatment selection and confounding are needed to assess these interventional prospects for surgery avoidance. (Research funding provided by Eli Lilly and Company, Indianapolis IN.)

Low back pain (LBP) treatment often entails step-therapy additions of medications (including antidepressants) and noninvasive therapies to remediate pain, improve functioning, and avoid surgery. We examine the role of duloxetine and other treatments in the likelihood of LBP surgery, adjusting for potential selection bias and confounding. The 211,551 patients, ages 18-64 years, with >1 LBP diagnosis, as specified by HEDIS, were identified from a large administrative insured claims database. Patients had continuous eligibility at least 12 months after their index LBP diagnosis (study period) and >6 months before their index diagnosis (baseline period) and no other LBP diagnosis during the baseline period. 4,331 patients (2.05%) had back surgery, and 3,756 (1.78%) patients received duloxetine, after their index LBP diagnosis. Logistic regression was used to develop a propensity score predicting study period duloxetine use using: demographics; baseline comorbidities; resource use; medication use; and direct costs. Patients receiving duloxetine were matched to LBP patients untreated with duloxetine based on propensity score and key confounders (e.g., baseline depression, baseline opioid use). Logistic regressions were conducted to assess the impact of study period treatments on back surgery risk for the full matched sample and the non-depressed subsample. We propensity matched 2,521 duloxetine patients to controls. In general, duloxetine was the last of all treatments (including opiates) initiated prior to surgery. Likelihood of surgery was significantly increased for patients with chronic LBP (<3 months) and severe LBP diagnoses. Three treatments significantly reduced the likelihood of surgery: NSAIDs, chiropractic therapy, and duloxetine. No other antidepressants, anxiolytics, narcotics, relaxants, anti-epileptics, or corticosteroids predicted surgery. Results for treatments were the same in the non-depressed subsample. Duloxetine, NSAIDs, and chiropractic treatments were associated with reduced likelihood of LBP surgery. (Research funding provided by Eli Lilly and Company.)