Search

Background No consensus exists regarding adequacy of margins after mastectomy. To determine if pathological margin proximity is associated with local (LR) or distant recurrence after mastectomy for early invasive breast cancer or ductal carcinoma in situ. Methods A systematic review of literature published from 1980 to 2019 and meta-analysis was conducted. Unpublished data were sought from authors (PROSPERO (CRD42019127541)). Thirty-four studies comprising 34,833 breast cancer patients were included in the quantitative synthesis. Eligible studies reported on patients undergoing curative mastectomy for cancer allowing estimation of outcomes in relation to margin status/width. The association between pathological margin status and local (LR) and distant recurrence was considered using random effects modelling. PRISMA guidelines were followed. Results Positive margins were associated with increased LR on multivariable analyses (HR, 2·64, (95%CI 2·01–3·46)) and LR was higher regardless of the distance of tumour from the margin defined as positive. After skin-sparing mastectomy, positive margins were associated with increased LR (HR 3·40, (95%CI 1·9–6·2)). In the 4 studies reporting distant recurrence, patients with involved margins had a higher risk (HR 1·53, (95%CI 1·03–2·25)). Conclusions Failure to achieve clear margins after mastectomy may increase the risks of local and distant recurrence. Adequate margin clearance should be recommended to minimize recurrence after mastectomy in National and International Guidelines.

Background: Leaving involved margins after mastectomy for breast cancer has been associated with an increased risk of local recurrence. Current guidelines endorse a policy that negative margins of no ink on tumour represent sufficient margin for local control and that the routine practice of obtaining a more widely negative margin is not indicated. We performed a systematic review of the literature and meta-analysis of studies analysing the impact of margin involvement after mastectomy on subsequent local recurrence. Methods: A systematic review was carried out searching MedLine, EmBase and ProQuest databases using the terms ‘mastectomy’, ‘resection margin’, ‘deep margin’, ‘margin status’ ‘fascia’ and ‘muscle invasion or infiltration’ from 1980 - 2019. In total 2,199 papers were screened and 33 studies were included in the quantitative synthesis. Statistical Methods: Meta-analysis was conducted using random effects modelling, pooling hazard ratios (HR), and odds ratios (OR) from binary outcome data. The associations between positive margins and local recurrence were stratified by positive margin distance and analysed according to use of adjuvant radiotherapy and follow up duration. Results: In total 37,738 patients, with a median age of 54.5 years, were included in the quantitative synthesis. Positive margins were associated with increased local recurrence on univariable analyses (HR 2.99, 95%CI: 2.99, 2.15 - 4.15), multivariable adjusted analyses (HR, 2.61, (95%CI 2.03-3.35) (which included Molecular Phenotype, Stage and Node status) as well as binary outcome data (OR, 95%CI: 2.75, 1.94-3.88). Positive margins were consistently associated with increased local recurrence, regardless of the distance of the tumour from the margin defined as positive (HR, 95%CI, tumour at ink: 2.39, 1.53-3.72; margin 5 years compared to 5 years OR 3.50, 2.13 - 5.75). Data were available from five studies for patients not receiving radiotherapy. In this subgroup positive margins were associated with a 3-fold risk of local recurrence (OR: 3.01, 1.96-4.61). Conclusions: On meta-analysis the risk of local recurrence after mastectomy is associated with margin proximity. Most data on margin status has related to breast conserving surgery. Adequate surgical margin clearance greater than 2mm margin after mastectomy is required to prevent local recurrence and International guidelines should reflect this finding. Citation Format: James Bundred, Sarah Michael, Sarah Bowers, Nicola Barnes, David Dodwell, Yasmin Jauhari, Nigel Bundred. Do surgical margins matter after mastectomy? A meta-analysis of 37,738 breast cancer patients in 33 studies [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-20-07.

Background: Leaving involved margins after surgery for early breast cancer is associated with an increased risk of local recurrence but the effect on distant recurrence is controversial. ASCO and ASTRO endorsed a policy that negative margins of no ink on tumour represented sufficient margin for local control and that the routine practice of obtaining a more widely negative margin was not indicated. We aimed to assess margin status (2mm) on local and distant control of breast cancer in a consecutive UK patient audit of Breast Cancer Units. Methods: Patients (n = 2795) undergoing surgery for early breast cancer (Tis, T1-3) in 3 Greater Manchester Breast Units had margin status prospectively recorded (reported by micrometer according to NHSBSP pathology guidelines) and local and distant recurrence recorded. All patients received adjuvant therapy according to local guidelines. Statistical analysis using cox proportional hazard regression was used to identify clinicopathological factors predicting recurrence in the multivariate analysis. Results: Overall 575 women (19.3%) had involved (≤1mm clearance) and 235 (8.5%) close (≤2mm clearance) and 1895 clear surgical margins. 1652 patients underwent breast conserving surgery and 1143 mastectomy. Median follow-up is 63.7 months. Overall local recurrence rate was 3.8% and distant recurrence 4.9% by a median of 5 years follow-up. Local and distant recurrence was higher after mastectomy at 7% and 7.8%, respectively. Margin 2mm. In multivariate analysis, two factors: molecular phenotype (other phenotypes versus Luminal A HR 1.79) and close / involved margins less than 2mm clearance (versus clear >2mm) [HR 1.76 (95% confidence intervals 1.06 - 2.92)], predicted local recurrence and the same factors together with mastectomy (compared to breast conservation), T and N stage predicted distant recurrence (see table 1). Table 1. Multivariate analysis of factors predicting cancer recurrenceLocal Recurrence (HR)Distant Recurrence (HR)Margin categorical 2mm1.84 (1.05 - 3.22, p=0.031)1.82 (1.1 – 3.02, p= 0.019)Margin 2mm)1.76 (1.06-2.92, p=0.027)1.86 (1.16-2.27, p=0.009)T Stage 2 vs 11.55 (0.88 – 2.73, p=0.129)4.35 (2.07 – 9.14, p Conclusion: Clearing surgical margins improves recurrence free survival (both local and distant). Leaving margins ≤2mm increases distant cancer recurrence and clearance of margins should be essential surgical management, particularly in oestrogen receptor (ER) negative breast cancer. Current guidelines accepting margins ≤1mm will increase distant recurrence and deaths from breast cancer. Citation Format: Sarah Michael, Sarah Bowers, Jane Ooi, Mo Absar, James Bundred, Nigel Bundred. Surgical margin involvement (

Objective: To identify variables that correlate with sexual satisfaction and sexual distress among adult cancer survivors, and how these differ, providing a basis from which approaches to intervention may be identified. This study examined four key variables: body image disruption, self-compassion, relationship satisfaction and sexual pain previously, all linked to sexual quality of life. Methods: A cross-sectional survey was conducted online, with participants (n = 113) recruited via cancer charities, support groups, and sexual counsellors’ networks. A multivariate multiple regression analysis was conducted to analyse relationships among variables. Results: In a regression adjusted for age and sex and time since diagnosis, higher sexual distress was significantly associated with higher body image disruption (β =0.23; p = .042), lower self-compassion (β = 0.29; p = .009), and higher sexual pain (β = 0.39; p < .001); but not relationship satisfaction (β =-0.08; p = .433). Higher sexual satisfaction was significantly associated with higher relationship satisfaction (β = 0.35; p = .002) and lower sexual pain (β = -0.29; p = .004), but not body image disruption (β = -0.19; p = .089), or self-compassion (β = 0.06; p = .614). Sexual pain had a significantly stronger association with sexual distress than sexual satisfaction; F (1, 87) = 18.29, p < .001. Conclusions: Sexual distress and sexual satisfaction are associated with different psycho-social correlates even though both are used as indicators of sexual health. Research should seek to further understand the differences in these two critical markers of sexual health, with these differences likely to highlight the need to match interventions to the nature of the sexual difficulties experienced following cancer treatment. Refereed/Peer-reviewed

ObjectivesCardiovascular disease is the leading cause of premature death in patients with mental illness. Metabolic syndrome is a cluster of co-occurring cardiovascular risk factors, seen in high frequency in severe mental illness. Despite ease of diagnosis, monitoring is often poor across psychiatric populations. This report details a quality improvement initiative undertaken on an inpatient psychiatric ward to improve rates of metabolic monitoring.MethodsFour key interventions were developed: (1) A nurse-led intervention, where nurses were upskilled in performing metabolic monitoring, (2) Education was provided to all staff, (3) Introduction of a suite of interventions to improve metabolic risk and (4) Ongoing consumer involvement. A pre–post intervention study design was used to measure effectiveness, with an audit of metabolic monitoring rates performed 12 months after the intervention began.ResultsRates of weight and height monitoring both increased from 46.0% to 69.5% (p=0.0185) and body mass index (BMI) recordings increased from 33% to 63% (p=0.0031). Rates of waist circumference monitoring increased from 44.2% to 65.2% (p=0.0498). Blood pressure (BP) measurements increased from 88.5% to 100% (p=0.0188). Lipid monitoring rates improved from 23% to 69.5% (p=0.001). Rates of glucose monitoring increased from 74% to 82.5% (p=0.8256), although this was not statistically significant.ConclusionsWe found that metabolic monitoring improved following these simple interventions, with a statistically significant increase in measurement rates of weight, BP, height, lipids, BMI and waist circumference (p

Background Integrating exercise professionals into mental health settings is a key strategy in addressing the physical health inequalities of people living with mental illness. Workforce culture surrounding physical health may impact the utilisation of exercise professionals across inpatient settings. Aims To evaluate clinician perspectives regarding the implementation of an exercise professional at the mental health service in a large, urban hospital in Sydney, Australia. Methods A qualitative study using semi-structured interviews with a purposive sample of mental health staff was conducted. Data were analysed using thematic analysis. Results Fourteen mental health clinicians (approximately 35% of all eligible staff) participated in interviews. Three themes emerged regarding the role of the exercise professional; i) drivers and facilitators; ii) support from leadership; and iii) directions for future practice. Conclusions An exercise professional within a mental health service was identified as an effective strategy in improving consumer health outcomes while increasing the knowledge and confidence of mental health clinicians regarding the provision of physical health care. Exercise professionals should be recognised as important members of the standard multidisciplinary mental health team for in patients being treated for mental illness.

Mental health providers experience inappropriate sexual behavior from patients. It is unclear if training programs adequately prepare trainees to respond to such behaviors. Additionally, trainees may not seek support and guidance from supervisors after an incident. This is an exploratory study to document the prevalence of and assess the preparedness of trainees to deal with inappropriate sexual behavior. A survey was administered to 58 psychiatry residents and 14 psychology interns at the NYU School of Medicine. A total of 22 questions were asked regarding participants’ experiences with inappropriate sexual behavior, including prevalence of, and preparedness during, and support received after the behavior. Of those who completed the survey, 89% of respondents had experienced inappropriate sexual behavior. Seventy percent said they had no training in responding to inappropriate sexual behavior, and 95% wanted more training. A minority of respondents consistently sought support after these events, and of those who did, only 60% of trainees did so with a supervisor. Experiences involving inappropriate sexual behavior are prevalent among the mental health trainees surveyed, but most trainees did not feel that they received adequate training in preparation for or supervision after their experiences. Creating training or establishing protocols to respond to inappropriate sexual behavior may help trainees feel more capable and safer. Further studies are needed to understand inappropriate sexual behavior’s impact on trainees and patient care, as well as to assess the efficacy of training and protocols developed to manage inappropriate sexual behavior.

Parkinson's disease and dementia with Lewy bodies are neurodegenerative disorders characterized by accumulation of α-synuclein (α-syn). Recently, single-chain fragment variables (scFVs) have been developed against individual conformational species of α-syn. Unlike more traditional monoclonal antibodies, these scFVs will not activate or be endocytosed by Fc receptors. For this study, we investigated an scFV directed against oligomeric α-syn fused to the LDL receptor-binding domain from apolipoprotein B (apoB). The modified scFV showed enhanced brain penetration and was imported into neuronal cells through the endosomal sorting complex required for transport (ESCRT) pathway, leading to lysosomal degradation of α-syn aggregates. Further analysis showed that the scFV was effective at ameliorating neurodegenerative pathology and behavioral deficits observed in the mouse model of dementia with Lewy bodies/Parkinson's disease. Thus, the apoB modification had the effect of both increasing accumulation of the scFV in the brain and directing scFV/α-syn complexes for degradation through the ESCRT pathway, leading to improved therapeutic potential of immunotherapy.

Many neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are characterized by abnormal accumulations of aggregated proteins. Brains in these diseases also show accumulation of autophagic vesicles in the neuronal cytoplasm, suggesting impairment of the autophagic process. As autophagy involves de novo membrane production and vesicle fusion, extensive changes in lipid molecules are necessary. However, the involvement of signaling lipid-modifying enzymes in autophagy and their roles in neurodegenerative diseases are not clear. Using specific inhibitor, we show that loss of phospholipase D1 (PLD1) activity resulted in an accumulation of microtubule-associated protein light chain 3 (LC3), p62, and polyubiquitinated proteins, signs representing malfunction in autophagic flux. Fluorescence and electron microscopic analyses demonstrated impaired fusion of autophagosomes with lysosomes, resulting in accumulation of autophagosomes. Within the cells with impaired autophagic flux, α-synuclein aggregates accumulated in autophagosomes. Knockdown of PLD1 expression using small interfering RNA also resulted in impaired autophagic flux and accumulation of α-synuclein aggregates in autophagosomes. Neuronal toxicity caused by α-synuclein accumulation was rescued by overexpression of PLD1; however, expression of activity-deficient mutant, PLD1-KRM, showed reduced rescue effects. Finally, we demonstrated that both PLD activity and expression levels were reduced in brain tissues of dementia with Lewy bodies (DLB) patients, whereas the amounts of α-synuclein and p62 were increased in the same tissue samples. Collectively, these results suggest that insufficient PLD activity, and therefore, the changes in phospholipid compositions within membranes, might be an important contributor to impaired autophagic process and protein accumulation in Lewy body diseases.

Since the discovery and isolation of α-synuclein (α-syn) from human brains, it has been widely accepted that it exists as an intrinsically disordered monomeric protein. Two recent studies suggested that α-syn produced in Escherichia coli or isolated from mammalian cells and red blood cells exists predominantly as a tetramer that is rich in α-helical structure (Bartels, T., Choi, J. G., and Selkoe, D. J. (2011) Nature 477, 107-110; Wang, W., Perovic, I., Chittuluru, J., Kaganovich, A., Nguyen, L. T. T., Liao, J., Auclair, J. R., Johnson, D., Landeru, A., Simorellis, A. K., Ju, S., Cookson, M. R., Asturias, F. J., Agar, J. N., Webb, B. N., Kang, C., Ringe, D., Petsko, G. A., Pochapsky, T. C., and Hoang, Q. Q. (2011) Proc. Natl. Acad. Sci. 108, 17797-17802). However, it remains unknown whether or not this putative tetramer is the main physiological form of α-syn in the brain. In this study, we investigated the oligomeric state of α-syn in mouse, rat, and human brains. To assess the conformational and oligomeric state of native α-syn in complex mixtures, we generated α-syn standards of known quaternary structure and conformational properties and compared the behavior of endogenously expressed α-syn to these standards using native and denaturing gel electrophoresis techniques, size-exclusion chromatography, and an oligomer-specific ELISA. Our findings demonstrate that both human and rodent α-syn expressed in the central nervous system exist predominantly as an unfolded monomer. Similar results were observed when human α-syn was expressed in mouse and rat brains as well as mammalian cell lines (HEK293, HeLa, and SH-SY5Y). Furthermore, we show that α-syn expressed in E. coli and purified under denaturing or nondenaturing conditions, whether as a free protein or as a fusion construct with GST, is monomeric and adopts a disordered conformation after GST removal. These results do not rule out the possibility that α-syn becomes structured upon interaction with other proteins and/or biological membranes.

Background Studies at the behavioral and synaptic level show that effects of ethanol on the central nervous system can involve the opioid signaling system. These interactions may alter the function of a common downstream target. In this study, we examined Ca2+ channel function as a potential downstream target of interactions between ethanol and mu or kappa opioid receptor signaling.

DNA methylation is a major epigenetic modification that regulates gene expression. Dnmt1, the maintenance DNA methylation enzyme, is abundantly expressed in the adult brain and is mainly located in the nuclear compartment, where it has access to chromatin. Hypomethylation of CpG islands at intron 1 of the SNCA gene has recently been reported to result in overexpression of α-synuclein in Parkinson disease (PD) and related disorders. We therefore investigated the mechanisms underlying altered DNA methylation in PD and dementia with Lewy bodies (DLB). We present evidence of reduction of nuclear Dnmt1 levels in human postmortem brain samples from PD and DLB patients as well as in the brains of α-synuclein transgenic mice models. Furthermore, sequestration of Dnmt1 in the cytoplasm results in global DNA hypomethylation in human and mouse brains, involving CpG islands upstream of SNCA, SEPW1, and PRKAR2A genes. We report that association of Dnmt1 and α-synuclein might mediate aberrant subcellular localization of Dnmt1. Nuclear Dnmt1 levels were partially rescued by overexpression of Dnmt1 in neuronal cell cultures and in α-synuclein transgenic mice brains. Our results underscore a novel mechanism for epigenetic dysregulation in Lewy body diseases, which might underlie the decrease in DNA methylation reported for PD and DLB.

Introduction Methods for improving patient safety are predicated on cooperation between healthcare groups, but are the views of health professionals involved in promoting safety shared by other healthcare workforce staff and managers? Aim To compare patient-safety suggestions from health workforce managerial and staff groups with those of patient-safety specialists. Method Samples of managers (424) and staff (1214) in the South Australian state health system and 131 Australian patient-safety specialists were asked to write suggestions for improving patient safety. Group responses were content analysed and compared. Results Patient-safety specialists (83.2%) were more likely to make suggestions than were workforce managers (57.8%) or staff (44.1%). Workforce members from clinical professions were more likely than non-clinicians to tender suggestions. No relationship existed between the importance specialists and managers (ρ=−0.062, p=0.880) and specialists and staff (ρ=−0.046, p=0.912) attached to nine categories of suggestions. There was a high correlation between the importance that managers and non-managers attached to safety strategies (ρ=0.817, p=0.011). Among those who made suggestions, specialists were more likely to suggest implementing reviews and guidelines, and incident reporting. Workforce groups were more likely to recommend increased and improved staffing and staffing conditions, and better equipment and infrastructure. There were no significant differences in the proportions of group members recommending: improving management and leadership; increasing staff safety education and supervision; communication and teamwork; improved patient focus; or tackling specific safety projects. Implications Differences between safety specialists' and workforce groups' beliefs about how to improve patient safety may impede the successful implementation of patient-safety programmes.

In this analysis of the global workforce, the Joint Learning Initiative-a consortium of more than 100 health leaders-proposes that mobilisation and strengthening of human resources for health, neglected yet critical, is central to combating health crises in some of the world's poorest countries and for building sustainable health systems in all countries. Nearly all countries are challenged by worker shortage, skill mix imbalance, maldistribution, negative work environment, and weak knowledge base. Especially in the poorest countries, the workforce is under assault by HIV/AIDS, out-migration, and inadequate investment. Effective country strategies should be backed by international reinforcement. Ultimately, the crisis in human resources is a shared problem requiring shared responsibility for cooperative action. Alliances for action are recommended to strengthen the performance of all existing actors while expanding space and energy for fresh actors.

Abnormal aggregation of alpha-synuclein and sustained microglial activation are important contributors to the pathogenic processes of Parkinson's disease. However, the relationship between disease-associated protein aggregation and microglia-mediated neuroinflammation remains unknown. Here, using a combination of in silico, in vitro and in vivo approaches, we show that extracellular alpha-synuclein released from neuronal cells is an endogenous agonist for Toll-like receptor 2 (TLR2), which activates inflammatory responses in microglia. The TLR2 ligand activity of alpha-synuclein is conformation-sensitive; only specific types of oligomer can interact with and activate TLR2. This paracrine interaction between neuron-released oligomeric alpha-synuclein and TLR2 in microglia suggests that both of these proteins are novel therapeutic targets for modification of neuroinflammation in Parkinson's disease and related neurological diseases.

Neurosin is a predominant serine protease in the central nervous system (CNS) and has been shown to play a role in the clearance of α-synuclein (α-syn) which is centrally involved in the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Although it has been previously shown that neurosin and α-syn colocalize and that neurosin degrades α-syn aggregates in vitro, it is not clear if neurosin is dysregulated in the brains of patients with PD/DLB and to what extent delivery of neurosin into the CNS might ameliorate the deficits associated with α-syn accumulation in vivo. We analyzed the levels of neurosin in the brains of patients with PD/DLB and in α-syn transgenic (tg) models. With increased accumulation of α-syn, we observed decreased neurosin expression. Lentiviral vector (LV) driven expression of neurosin in neuronal cell cultures reduced the accumulation of wild type but not A53T α-syn and prevented α-syn associated toxicity. Neuropathological analysis following delivery of LV-Neurosin to α-syn tg mice resulted in reduced accumulation of α-syn and reversal of neurodegenerative alterations in wild type but not A53T α-syn tg mice. Therefore, viral vector driven expression of neurosin may warrant further investigation as a potential therapeutic tool for DLB.

The neurodegenerative pathology in patients with Alzheimer’s disease (AD) has been associated with the progressive accumulation of aggregated and post-translationally modified amyloid-β (Aβ) species. Among them, recent studies indicate that the pyroglutamate modification of Aβ (pE(3)Aβ) catalyzed by glutaminyl cyclase might play an important role in the pathogenesis of AD. Although the effects of the pyroglutamate modification on Aβ aggregation and toxicity have been investigated, less is known about the distribution of pE(3)Aβ across the spectrum of AD and in the brains of amyloid-β protein precursor (AβPP) transgenic (tg) animals. For this purpose, we generated a novel monoclonal antibody (denominated D129) that specifically recognizes pE(3)Aβ and characterized the patterns of distribution in the postmortem brain samples from AD patients divided by disease stage (Braak stage) and in AβPP tg mice. We found that in early stages of AD and young AβPP tg mice pE(3)Aβ was found in discrete linear and granular aggregates in the neuropil that co-localized with the pre-synaptic protein synaptophysin and was in close opposition to dendrites labeled with MAP2. In later stages of AD and in older AβPP tg mice, pE(3)Aβ was abundant in diffuse and mature plaques. In conclusion, this study suggests that peri-synaptic accumulation of pE(3)Aβ might contribute to early cognitive dysfunction in AD.

Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by the loss of neurotrophic factors, and experimental therapeutical approaches to AD have investigated the efficacy of replacing or augmenting neurotrophic factor activity. Cerebrolysin, a peptide mixture with neurotrophic-like effects, has been shown to improve cognition in patients with AD and to reduce synaptic and behavioral deficits in transgenic (tg) mice overexpressing the amyloid precursor protein (APP). However, it is unclear how long-lasting the beneficial effects of Cerebrolysin are and whether or not behavioral and neuropathological alterations will reappear following treatment interruption. The objective of the present study was to investigate the consequences of interrupting Cerebrolysin treatment (washout effect) 3 and 6 months after the completion of a 3-month treatment period in APP tg mice. We demonstrate that, in APP tg mice, Cerebrolysin-induced amelioration of memory deficits in the water maze and reduction of neurodegenerative pathology persist for 3 months after treatment interruption; however, these effects dissipate 6 months following treatment termination. Immunohistochemical analysis demonstrated that the decrease in neocortical and hippocampal amyloid plaque load observed in Cerebrolysin-treated APP tg mice immediately after treatment was no longer apparent at 3 months after treatment interruption, indicating that the beneficial effects of Cerebrolysin at this time point were independent of its effect on amyloid-β deposition. In conclusion, the results demonstrate that the effects of Cerebrolysin persist for a significant period of time following treatment termination and suggest that this prolonged effect may involve the neurotrophic factor-like activity of Cerebrolysin. © 2011 Wiley-Liss, Inc.

Falls are a common and serious health problem. Responses to the problem should address the individual, the individual's environment, the system of health or residential care used by the individual, and the local community. This article describes a response to the issue of falls in Ryde Hospital and its surrounding community. This response has multiple components which include patient and staff education and interventions with people who have fallen. These initiatives have been developed without additional resources and incorporated into existing systems of care provision.

Alzheimer's disease (AD), an incurable, progressive neurodegenerative disorder, is the most common form of dementia. Therapeutic options have been elusive due to the inability to deliver proteins across the blood-brain barrier (BBB). In order to improve the therapeutic potential for AD, we utilized a promising new approach for delivery of proteins across the BBB. We generated a lentivirus vector expressing the amyloid β-degrading enzyme, neprilysin, fused to the ApoB transport domain and delivered this by intra-peritoneal injection to amyloid protein precursor (APP) transgenic model of AD. Treated mice had reduced levels of Aβ, reduced plaques and increased synaptic density in the CNS. Furthermore, mice treated with the neprilysin targeting the CNS had a reversal of memory deficits. Thus, the addition of the ApoB transport domain to the secreted neprilysin generated a non-invasive therapeutic approach that may be a potential treatment in patients with AD.