for Alzheimer’s disease.

Background: Convergent evidence indicates that deficits in the endosomal recycling pathway underlies pathogenesis of Alzheimer’s disease (AD). encodes the retromer‐associated receptor SORLA that plays an essential role in recycling of AD‐associated cargos such as the amyloid precursor protein and the glutamatergic AMPA receptor. Importantly, loss of function pathogenic variants are associated with AD.

The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease.

Disruption of retromer-dependent endosomal trafficking is considered pathogenic in late-onset Alzheimer's disease (AD). Here, to investigate this disruption in the intact brain, we turn to a genetic mouse model where the retromer core protein VPS35 is depleted in hippocampal neurons, and then we replete VPS35 using an optimized viral vector protocol. The VPS35 depletion-repletion studies strengthen the causal link between the neuronal retromer and AD-associated neuronal phenotypes, including the acceleration of amyloid precursor protein cleavage and the loss of synaptic glutamate receptors.

Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling.

Whether and how the pathogenic disruptions in endosomal trafficking observed in Alzheimer's disease (AD) are linked to its anatomical vulnerability remain unknown. Here, we began addressing these questions by showing that neurons are enriched with a second retromer core, organized around VPS26b, differentially dedicated to endosomal recycling. Next, by imaging mouse models, we show that the trans-entorhinal cortex, a region most vulnerable to AD, is most susceptible to VPS26b depletion-a finding validated by electrophysiology, immunocytochemistry, and behavior.

Tau and other proteins found in Alzheimer's disease spinal fluid are linked to retromer-mediated endosomal traffic in mice and humans.

Endosomal trafficking has emerged as a defective biological pathway in Alzheimer's disease (AD), and the pathway is a source of cerebrospinal fluid (CSF) protein accumulation. Nevertheless, the identity of the CSF proteins that accumulate in the setting of defects in AD's endosomal trafficking pathway remains unknown. Here, we performed a CSF proteomic screen in mice with a neuronal-selective knockout of the core of the retromer complex VPS35, a master conductor of endosomal traffic that has been implicated in AD.

Endosomal Trafficking in Alzheimer's Disease, Parkinson's Disease, and Neuronal Ceroid Lipofuscinosis.

Neuronal ceroid lipofuscinosis (NCL) is one of the most prevalent neurodegenerative disorders of early life, Parkinson's disease (PD) is the most common neurodegenerative disorder of midlife, while Alzheimer's disease (AD) is the most common neurodegenerative disorder of late life. While they are phenotypically distinct, recent studies suggest that they share a biological pathway, retromer-dependent endosomal trafficking. A retromer is a multimodular protein assembly critical for sorting and trafficking cargo out of the endosome.

An Alzheimer's Disease-Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation, Consistent with a Retromer Trafficking Defect.

In a whole-exome sequencing study of multiplex Alzheimer's disease (AD) families, we investigated three neuronal ceroid lipofuscinosis genes that have been linked to retromer, an intracellular trafficking pathway associated with AD: ceroid lipofuscinosis 3 (CLN3), ceroid lipofuscinosis 5 (CLN5), and cathepsin D (CTSD). We identified a missense variant in CLN5 c.A959G (p.

Local control and overall survival for adjuvant stereotactic radiosurgery in patients with residual or recurrent disease.

Prior studies of post-operative stereotactic radiosurgery (SRS) have not distinguished between Adjuvant SRS (ARS) versus Adjuvant SRS to residual/recurrent disease (ARD). In this study, we defined ARS and ARD and investigated local control (LC), overall survival (OS), distant development of brain metastases (DBF), and leptomeningeal disease (LMD). We retrospectively identified BM patients who received surgical resection and SRS for BM from an IRB approved database between Jan 2009-Aug 2015.

Effects of baseline and early acquired thrombocytopaenia on long-term mortality in patients undergoing percutaneous coronary intervention with bivalirudin.

Aims: Bivalirudin use as a procedural anticoagulant in patients undergoing percutaneous coronary intervention (PCI) is associated with a lower incidence of thrombocytopaenia compared to other antithrombotic agents. We aimed to evaluate the prognostic impact of baseline thrombocytopaenia and early changes in platelet counts among patients undergoing PCI with exclusive use of bivalirudin.

Methods And Results: We evaluated 7,505 patients who underwent PCI over a period of eight years.

Hypofractionated radiation therapy versus standard fractionated radiation therapy with concurrent temozolomide in elderly patients with newly diagnosed glioblastoma.

Purpose: Adjuvant hypofractionated radiation therapy (HRT) for elderly patients with newly diagnosed glioblastoma (GBM) is a reasonable option compared with standard fractionation radiation therapy (SFRT). Outcomes in patients receiving HRT in the presence of temozolomide (TMZ) compared with SFRT with TMZ are unclear. We examined HRT for GBM with TMZ in comparison to SFRT with TMZ.

A Modern Radiotherapy Series of Survival in Hispanic Patients with Glioblastoma.

Background: Studies have shown racial differences in cancer outcomes. We investigate whether survival differences existed in Hispanic patients with glioblastoma (GBM) compared with other ethnicities from our modern radiotherapy series, because no study to date has focused on outcomes in this group after radiation therapy.

Methods: We retrospectively evaluated 428 patients diagnosed with GBM from 1996 to 2014 at our institution, divided into 4 groups based on self-report: white, black, Hispanic, and Asian/Indian.

Breast cancer subtype as a predictor for outcomes and control in the setting of brain metastases treated with stereotactic radiosurgery.

We investigated effects of breast cancer subtype on overall survival (OS), local and distant control, and time from initial diagnosis to brain metastases (BM). We also investigated advances in graded prognostic assessment (GPA) scores. A cohort of 72 patients treated for BM from breast cancer with Gamma Knife stereotactic radiosurgery at our institution from 2000 to 2014 had subtyping available and were used for this study.

Timing of Adjuvant Radiotherapy in Glioblastoma Patients: A Single-Institution Experience With More Than 400 Patients.

Background: The standard of care for patients with newly diagnosed glioblastoma (GBM) is maximal safe resection followed by adjuvant radiation therapy (RT) and temozolomide (TMZ).

Objective: To investigate whether the timing of adjuvant RT after surgery affected outcome in patients with GBM.

Methods: We retrospectively reviewed all patients with a diagnosis of GBM at our institution.

Does lung cancer mutation status and targeted therapy predict for outcomes and local control in the setting of brain metastases treated with radiation?

Background: We investigated effects of genetic alterations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS) on overall survival (OS) and local control after stereotactic radiosurgery for brain metastases in non-small cell lung cancer (NSCLC).

Methods: A cohort of 89 out of 262 NSCLC patients (2003-2013) treated with gamma knife radiosurgery for brain metastases had genotyping available and were selected as our study population.

Results: Median follow-up was 12 months.

The Energy Index Does Not Affect Local Control of Brain Metastases Treated by Gamma Knife Stereotactic Radiosurgery.

Background: The energy index (EI) is a measure of dose homogeneity within a target volume calculated by the integral dose divided by the product of prescription dose and tumor volume.

Objective: To assess whether a higher EI is associated with greater local control for brain metastases (BMs) treated by Gamma Knife radiosurgery (GKRS).

Methods: We reviewed all patients treated with GKRS for BM at our institution between January 2009 and February 2014.

Assembly and interrogation of Alzheimer's disease genetic networks reveal novel regulators of progression.

Alzheimer's disease (AD) is a complex multifactorial disorder with poorly characterized pathogenesis. Our understanding of this disease would thus benefit from an approach that addresses this complexity by elucidating the regulatory networks that are dysregulated in the neural compartment of AD patients, across distinct brain regions. Here, we use a Systems Biology (SB) approach, which has been highly successful in the dissection of cancer related phenotypes, to reverse engineer the transcriptional regulation layer of human neuronal cells and interrogate it to infer candidate Master Regulators (MRs) responsible for disease progression.

Outcomes of gamma knife radiosurgery, bi-modality & tri-modality treatment regimens for patients with one or multiple brain metastases: the Columbia University Medical Center experience.

Optimal treatment of brain metastases (BMs) is debatable. However, surgery or gamma knife radiosurgery (GKRS) improves survival when combined with whole brain radiotherapy (WBRT) versus WBRT alone. We retrospectively reviewed an institutional database of patients treated with GKRS for BMs from 1998 to 2013 to explore effects of single or multi-modality therapies on survival.

Promoting autophagic clearance: viable therapeutic targets in Alzheimer's disease.

Many neurodegenerative disorders are characterized by the aberrant accumulation of aggregate-prone proteins. Alzheimer's disease (AD) is associated with the buildup of β-amyloid peptides and tau, which aggregate into extracellular plaques and neurofibrillary tangles, respectively. Multiple studies have linked dysfunctional intracellular degradation mechanisms with AD pathogenesis.

Optical coherence tomography for guiding wire into a side branch coronary artery with flush total occlusion.

We report a case of flush occlusion, where a novel use of optical coherence tomography (OCT) helped in successful crossing and stenting of the lesion.

Impact of major bleeding on long-term mortality in anemic versus nonanemic patients undergoing percutaneous coronary intervention using bivalirudin.

Bleeding complications after percutaneous coronary intervention (PCI) have been associated with higher short and long-term mortality. Bivalirudin has been shown to reduce bleeding complications in patients who underwent PCI; however, the impact of anemia on bleeding complications and long-term mortality has not been studied. A total of 11,991 patients who underwent PCI over a period of 8 years with bivalirudin as the primary antithrombotic agent were included.