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Non-beta-amyloid/tau cerebrospinal fluid markers inform staging and progression in Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by neuropathologic changes involving beta-amyloid (Aβ), tau, neuronal loss, and other associated biological events. While levels of cerebrospinal fluid (CSF) Aβ and tau peptides have enhanced the antemortem detection of AD-specific changes, these two markers poorly reflect the severity of...

Human fibroblast and stem cell resource from the Dominantly Inherited Alzheimer Network

. Morris 6 Randall J. Bateman 6 the Dominantly Inherited Alzheimer Network (DIAN) Alice P?bay 2 3 Alison M. Goate 1 4 0 Department of Psychiatry, Washington University School of Medicine , Campus Box 8134

Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structure

BackgroundAlzheimer’s disease (AD) is characterized by neuronal loss and astrocytosis in the cerebral cortex. However, the specific effects that pathological mutations and coding variants associated with AD have on the cellular composition of the brain are often ignored.MethodsWe developed and optimized a cell-type-specific expression reference panel and employed digital...

Discovery and validation of autosomal dominant Alzheimer’s disease mutations

BackgroundAlzheimer’s disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. Mutations in amyloid-β precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the pathogenic cause of autosomal dominant AD (ADAD). However, polymorphisms also exist within these genes.MethodsIn order to distinguish...

On the path to 2025: understanding the Alzheimer’s disease continuum

Basic research advances in recent years have furthered our understanding of the natural history of Alzheimer’s disease (AD). It is now recognized that pathophysiological changes begin many years prior to clinical manifestations of disease and the spectrum of AD spans from clinically asymptomatic to severely impaired. Defining AD purely by its clinical presentation is thus...

Association of Functional Impairments and Co-Morbid Conditions with Driving Performance among Cognitively Normal Older Adults

Objectives To examine the relationship between key functional impairments, co-morbid conditions and driving performance in a sample of cognitively normal older adults. Design Prospective observational study Setting The Knight Alzheimer’s Disease Research Center, Washington University at St. Louis Participants Individuals with normal cognition, 64.9 to 88.2 years old (N = 129...

Longitudinal Associations between Physical and Cognitive Performance among Community-Dwelling Older Adults

To assess the directionality of the association between physical and cognitive decline in later life, we compared patterns of decline in performance across groups defined by baseline presence of cognitive and/or physical impairment [none (n = 217); physical only (n = 169); cognitive only (n = 158), or both (n = 220)] in a large sample of participants in a cognitive aging study at...

Drug development in Alzheimer’s disease: the path to 2025

John C. Morris Joel Raskin Sherie A. Dowsett Philip Scheltens 0 Cleveland Clinic Lou Ruvo Center for Brain Health , Las Vegas, NV , USA The global impact of Alzheimer's disease (AD) continues to

A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies

bioavailability was quite low, which may be related to gastrointestinal-specific toxicity. The changes in steady-state pharmacokinetics of everolimus with BEZ235 highlight po- - * John C. Morris tential drug

Safety and pharmacokinetics of cabazitaxel in patients with hepatic impairment: a phase I dose-escalation study

conflicts of interest to disclose. Olivier Rixe has been a member of advisory boards for Areva Med and Sisene Oncology. John C. Morris has participated at speaker bureaus for Boehringer Ingelheim. Alain C

Lung cancer-initiating cells: a novel target for cancer therapy

Brian J. Morrison John C. Morris Jason C. Steel 0 ) Division of Hematology-Oncology, Vontz Center for Molecular Studies, Department of Internal Medicine, University of Cincinnati , 3125 Eden Ave., M

Sphere Culture of Murine Lung Cancer Cell Lines Are Enriched with Cancer Initiating Cells

Cancer initiating cells (CICs) represent a unique cell population essential for the maintenance and growth of tumors. Most in vivo studies of CICs utilize human tumor xenografts in immunodeficient mice. These models provide limited information on the interaction of CICs with the host immune system and are of limited value in assessing therapies targeting CICs, especially immune...

A survey of attitudes toward clinical trials and genetic disclosure in autosomal dominant Alzheimer’s disease

Introduction Because of its genetic underpinnings and consistent age of onset within families, autosomal dominant Alzheimer’s disease (ADAD) provides a unique opportunity to conduct clinical trials of investigational agents as preventative or symptom-delaying treatments. The design of such trials may be complicated by low rates of genetic testing and disclosure among persons at...

Quantitative Amyloid Imaging Using Image-Derived Arterial Input Function

Amyloid PET imaging is an indispensable tool widely used in the investigation, diagnosis and monitoring of Alzheimer’s disease (AD). Currently, a reference region based approach is used as the mainstream quantification technique for amyloid imaging. This approach assumes the reference region is amyloid free and has the same tracer influx and washout kinetics as the regions of...

Lack of an association of BDNF Val66Met polymorphism and plasma BDNF with hippocampal volume and memory

Brain-derived neurotrophic factor (BDNF) has been shown to be important for neuronal survival and synaptic plasticity in the hippocampus in nonhuman animals. The Val66Met polymorphism in the BDNF gene, involving a valine (Val) to methionine (Met) substitution at codon 66, has been associated with lower BDNF secretion in vitro. However, there have been mixed results regarding...

Cerebrospinal fluid VILIP-1 and YKL-40, candidate biomarkers to diagnose, predict and monitor Alzheimer’s disease in a memory clinic cohort

Introduction We examined the utility of cerebrospinal fluid (CSF) proteins, Chitinase-3-like protein 1 (CHI3L1 or YKL-40), a putative marker of inflammation, and Visinin-like protein-1 (VILIP-1), a marker for neuronal injury, for diagnostic classification and monitoring of disease progression in a memory clinic cohort. Methods CSF levels of YKL-40 and VILIP-1 were measured in 37...

Diurnal Patterns of Soluble Amyloid Precursor Protein Metabolites in the Human Central Nervous System

The amyloid-β (Aβ) protein is diurnally regulated in both the cerebrospinal fluid and blood in healthy adults; circadian amplitudes decrease with aging and the presence of cerebral Aβ deposits. The cause of the Aβ diurnal pattern is poorly understood. One hypothesis is that the Amyloid Precursor Protein (APP) is diurnally regulated, leading to APP product diurnal patterns. APP in...

Dominantly Inherited Alzheimer Network: facilitating research and clinical trials

thus houses all eight cores: Administration (John C Morris), Clinical (Randall Bateman), Biostatistics (Chengjie Xiong), Neuropathology (Nigel Cairns), Biomarker (Anne Fagan), Genetics (Alison Goate

Phase I Study of GC1008 (Fresolimumab): A Human Anti-Transforming Growth Factor-Beta (TGFβ) Monoclonal Antibody in Patients with Advanced Malignant Melanoma or Renal Cell Carcinoma

Background In advanced cancers, transforming growth factor-beta (TGFβ) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFβ monoclonal antibody that neutralizes all isoforms of TGFβ. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma. Methods In this multi...

Impacting tumor cell-fate by targeting the inhibitor of apoptosis protein survivin

Survivin (BIRC5), a member of the inhibitor of apoptosis protein (IAP) family that inhibits caspases and blocks cell death is highly expressed in cancer and is associated with a poorer clinical outcome. Functioning simultaneously during cell division and apoptosis inhibition, survivin plays a pivotal role in determining cell survival. Survivin has consistently been identified by...