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Spinal Fluid Biomarkers of AD and Brain Functional Network Integrity on Imaging Studies

Both Aß and tau pathology appear to be associated with default mode network integrity before clinical onset of Alzheimer disease (AD), according to a study by Liang Wang, M.D., and colleagues at Washington University in St. Louis, Missouri.

Accumulation of Aß and tau proteins, the pathologic hallmarks of AD, starts years before clinical onset. Pathophysiological abnormalities in the preclinical phase of AD may be detected using cerebrospinal fluid (CSF) or neuroimaging biomarkers, according to the study background.

A total of 207 older adults with normal cognition participated in the cross-sectional group study. Researchers examined the relationship between default mode network integrity and cerebrospinal fluid biomarkers of Alzheimer disease pathology in cognitively normal older individuals using resting-state functional connectivity magnetic resonance imaging.

According to the study results, decreased cerebrospinal fluid Aß42 and increased cerebrospinal fluid phosphorylated tau181 were independently associated with reduced default mode network integrity, with the most prominent decreases in functional connectivity observed between the posterior cingulate and medial temporal regions (regions of the brain associated with memory). Observed reductions in functional connectivity were unattributable to age or structural atrophy in the posterior cingulate and medial temporal areas.

Study: Cerebrospinal Fluid Aβ42, Phosphorylated Tau181, and Resting-State Functional Connectivity [JAMA Neurology]

Source: EurekAlert!

Alzheimer’s Markers Predict Start of Mental Decline

Scientists at Washington University School of Medicine in St. Louis have helped identify many of the biomarkers for Alzheimer’s disease that could potentially predict which patients will develop the disorder later in life. Now, studying spinal fluid samples and health data from 201 research participants at the Charles F. and Joanne Knight Alzheimer’s Disease Research Center, the researchers have shown the markers are accurate predictors of Alzheimer’s years before symptoms develop.

“We wanted to see if one marker was better than the other in predicting which of our participants would get cognitive impairment and when they would get it,” said Catherine Roe, PhD, research assistant professor of neurology. “We found no differences in the accuracy of the biomarkers.”

The study, supported in part by the National Institute on Aging, appears in Neurology.

The researchers evaluated markers such as the buildup of amyloid plaques in the brain, newly visible thanks to an imaging agent developed in the last decade; levels of various proteins in the cerebrospinal fluid, such as the amyloid fragments that are the principal ingredient of brain plaques; and the ratios of one protein to another in the cerebrospinal fluid, such as different forms of the brain cell structural protein tau.

The markers were studied in volunteers whose ages ranged from 45 to 88. On average, the data available on study participants spanned four years, with the longest recorded over 7.5 years.

The researchers found that all of the markers were equally good at identifying subjects who were likely to develop cognitive problems and at predicting how soon they would become noticeably impaired.

Next, the scientists paired the biomarkers data with demographic information, testing to see if sex, age, race, education and other factors could improve their predictions.

“Sex, age and race all helped to predict who would develop cognitive impairment,” Roe said. “Older participants, men and African Americans were more likely to become cognitively impaired than those who were younger, female and Caucasian.”

Roe described the findings as providing more evidence that scientists can detect Alzheimer’s disease years before memory loss and cognitive decline become apparent.

“We can better predict future cognitive impairment when we combine biomarkers with patient characteristics,” she said. “Knowing how accurate biomarkers are is important if we are going to some day be able to treat Alzheimer’s before symptoms and slow or prevent the disease.”

Clinical trials are already underway at Washington University and elsewhere to determine if treatments prior to symptoms can prevent or delay inherited forms of Alzheimer’s disease. Reliable biomarkers for Alzheimer’s should one day make it possible to test the most successful treatments in the much more common sporadic forms of Alzheimer’s.

Study: Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later

Source: EurekAlert!

Lilly Acquires Novel Tau Tangle Diagnostic Program to Bolster Alzheimer’s Disease Research and Development

Eli Lilly and Company (NYSE: LLY) recently announced it has acquired two investigational positron emission tomography (PET) tracers from Siemens Medical Solutions USA, Inc. The tracers are intended to image tau (or neurofibrillary) tangles in the brain, one of two known hallmarks of Alzheimer’s disease. Based on studies of samples obtained at autopsy, the amount and location of tau tangles in an Alzheimer’s disease patient’s brain is thought to correlate with the severity of the disease. There are currently no approved diagnostics to detect tau tangles in living patients, creating challenges for scientists working to understand the progression of the disease and how therapies may impact it.

Lilly will initially focus on incorporating this new technology into its anti-amyloid and anti-tau research and development (R&D) programs. Use of a tau tangle tracer could enable tailoring and early identification of at-risk patients, as well as potentially provide a marker for treatment response. Lilly also has the option to commercialize the tracers. The tracers will be developed and validated by a team at Avid Radiopharmaceuticals, Lilly’s wholly owned subsidiary focused on molecular imaging. Financial terms of the deal are not being disclosed.

“The acquisition of these tau tangle tracers builds on our 25-year commitment of investing in Alzheimer’s disease research and development to bring new medicines to patients facing the terrible consequences of Alzheimer’s disease,” said Jan M. Lundberg, Ph.D., executive vice president, science and technology, and president, Lilly Research Laboratories. “We are hopeful that this technology will both enhance our understanding of tau and its role in Alzheimer’s disease, and contribute to the development of our anti-amyloid and anti-tau based therapies to treat this disease.”

“PET imaging is a valuable tool in the fight against Alzheimer’s disease, and Siemens is committed to helping fight this growing threat to our aging population,” said James Williams, CEO, Siemens Molecular Imaging business unit. “Lilly’s continued development of these tau PET tracers combined with Siemens’ ongoing investment in innovative PET imaging solutions is another great example of how Siemens is collaborating with pharmaceutical companies in an effort to provide new hope to patients and their families.”

There are two defining pathologies linked to the development of Alzheimer’s disease: the accumulation of amyloid-beta protein that forms beta-amyloid plaques outside of neurons, and the accumulation of tau protein that forms tau tangles inside them.The formation of tau tangles is thought to block the transport of nutrients and essential molecules throughout the cell, leading to neurodegeneration, or the progressive loss of structure or function of neurons. The formation of tau tangles mostly occurs after beta-amyloid plaques have developed, but unlike beta-amyloid plaques the evolution of tau tangle pathology is believed to closely mirror cognitive decline.

Scientists theorize that both beta-amyloid plaques and tau tangles are required for the development of Alzheimer’s disease, with the accumulation of amyloid beta representing the early trigger that initiates the disease process and tau tangles playing a secondary but critical role in the process of neuronal toxicity and death. For this reason, Lilly has established R&D programs to explore both the amyloid and tau hypotheses. Today’s acquisition will inform and help progress Lilly’s multiple approaches to treating Alzheimer’s disease, with the goal of speeding innovation to patients worldwide.

Source: Eli Lilly

C2N Diagnostics, InterVivo Solutions, and inviCRO Announce Formation of Pre-Competitive Consortium to Develop, Standardize, and Validate Preclinical Aged Canine Model of Alzheimer’s Disease

C2N Diagnostics, InterVivo Solutions, and inviCRO (“Companies”) announced recently the formation of a pre-competitive consortium to develop, standardize, and validate an aged-canine model of Alzheimer’s disease (AD) progression. The multi-year collaboration is believed to be the first-of-its-kind. It will rely on the longitudinal measurement of disease-specific and clinically relevant biomarkers in canine aging. The study is modeled after the Alzheimer’s Disease Neuroimaging Initiative (ADNI) initiative in humans. The characterization of AD relevant biomarkers in a preclinical model of disease aims to create a robust and reliable method for the screening of candidate therapies that may prevent, slow, or reverse Alzheimer’s pathology and symptomology. Ultimately, the work from this collaboration intends to improve the translatability of Alzheimer’s preclinical drug development to human drug development.

In-vivo Study Shows CK1D Inhibitors Improve Cognition in Alzheimer’s Model

Proteome Sciences is pleased to announce that the in-vivo study of its proprietary CK1D inhibitor programme in Alzheimer’s disease was completed as anticipated in December 2012.