Posts tagged alzheimer

ScienceDaily (May 7, 2012) — Greater purpose in life may help stave off the harmful effects of plaques and tangles associated with Alzheimer’s disease, according to a new study by researchers at Rush University Medical Center.

Greater purpose in life may help stave off the harmful effects of plaques and tangles associated with Alzheimer’s disease, according to a new study. (Credit: © Nejron Photo / Fotolia)

The study is published in the May issue of the Archives of General Psychiatry.

"Our study showed that people who reported greater purpose in life exhibited better cognition than those with less purpose in life even as plaques and tangles accumulated in their brains," said Patricia A. Boyle, PhD.

"These findings suggest that purpose in life protects against the harmful effects of plaques and tangles on memory and other thinking abilities. This is encouraging and suggests that engaging in meaningful and purposeful activities promotes cognitive health in old age."

Boyle and her colleagues from the Rush Alzheimer’s Disease Center studied 246 participants from the Rush Memory and Aging Project who did not have dementia and who subsequently died and underwent brain autopsy. Participants received an annual clinical evaluation for up to approximately 10 years, which included detailed cognitive testing and neurological exams.

Participants also answered questions about purpose in life, the degree to which one derives meaning from life’s experiences and is focused and intentional. Brain plaques and tangles were quantified after death. The authors then examined whether purpose in life slowed the rate of cognitive decline even as older persons accumulated plaques and tangles.

While plaques and tangles are very common among persons who develop Alzheimer’s dementia (characterized by prominent memory loss and changes in other thinking abilities), recent data suggest that plaques and tangles accumulate in most older persons, even those without dementia. Plaques and tangles disrupt memory and other cognitive functions.

Boyle and colleagues note that much of the Alzheimer’s research that is ongoing seeks to identify ways to prevent or limit the accumulation of plaques and tangles in the brain, a task that has proven quite difficult. Studies such as the current one are needed because, until effective preventive therapies are discovered, strategies that minimize the impact of plaques and tangles on cognition are urgently needed.

"These studies are challenging because many factors influence cognition and research studies often lack the brain specimen data needed to quantify Alzheimer’s changes in the brain," Boyle said. "Identifying factors that promote cognitive health even as plaques and tangles accumulate will help combat the already large and rapidly increasing public health challenge posed by Alzheimer’s disease."

The Rush Memory and Aging Project, which began in 1997, is a longitudinal clinical-pathological study of common chronic conditions of aging. Participants are older persons recruited from about 40 continuous care retirement communities and senior subsidized housing facilities in and around the Chicago Metropolitan area. More than 1,500 older persons are currently enrolled in the study.

Source: Science Daily

May 7, 2012

A study on a handful of people with suspected mild Alzheimer’s disease (AD) suggests that a device that sends continuous electrical impulses to specific “memory” regions of the brain appears to increase neuronal activity. Results of the study using deep brain stimulation, a therapy already used in some patients with Parkinson’s disease and depression, may offer hope for at least some with AD, an intractable disease with no cure.

"While our study was designed mainly to establish safety, involved only six people and needs to be replicated on a larger scale, we don’t have another treatment for AD at present that shows such promising effects on brain function," said the study’s first author, Gwenn Smith, Ph.D., a professor in the Department of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine. The research, published in the Archives of Neurology, was conducted while Smith was on the faculty at the University of Toronto, and will be continuing at Toronto, Hopkins and other U.S. sites in the future. The study was led by Andres M. Lozano, chairman of the Department of Neurosurgery at the University of Toronto.

One month and one year after implanting a device that allows for continuous electrical impulses to the brain, Smith and her colleagues performed PET scans that detect changes in brain cells’ metabolism of glucose, and found that patients with mild forms of AD showed sustained increases in glucose metabolism, an indicator of neuronal activity. The increases, the researchers say, were larger than those found in patients who have taken the drugs currently marketed to fight AD progression. Other imaging studies have shown that a decrease in glucose metabolism over the course of a year is typical in AD. Alzheimer’s disease cannot be precisely diagnosed by brain biopsies until after death.

The team observed roughly 15 percent to 20 percent increases in glucose metabolism after one year of continuous stimulation. The increases were observed, to a greater extent, in patients with better outcomes in cognition, memory and quality of life. In addition, the stimulation increased connectivity in brain circuits associated with memory.

Deep brain stimulation (DBS) requires surgical implantation of a brain pacemaker, which sends electrical impulses to specific parts of the brain. For the study, surgeons implanted a tiny electrode able to deliver a low-grade electrical pulse close to the fornix, a key nerve tract in brain memory circuits. The researchers — most with the University of Toronto — reported few side effects in the six subjects they tested. Just as importantly, says Smith, was seeing that DBS appeared to reverse the downturn in brain metabolism that typically comes with AD.

AD is a progressive and lethal dementia that mostly strikes the elderly. It affects memory, thinking and behavior. Estimates vary, but experts suggest that as many as 5.1 million Americans may have AD and that, as baby boomers age, prevalence will skyrocket. Smith says decades of research have yet to lead to clear understanding of its causes or to successful treatments that stop progression.

The trial of DBS came about, Smith reports, when Lozano used DBS of the fornix to treat an obese man. The procedure, designed to target the regions of the brain involved in appetite suppression, unexpectedly had significant increases in his memory. Inspired, the scientists persisted through rigorous ethical and scientific approvals before their AD phase I safety study could begin.

Smith, who also is director of the Division of Geriatric Psychiatry and Neuropsychiatry at Johns Hopkins Bayview Medical Center, is an authority on mapping the brain’s glucose metabolism in aging and psychiatric disease. It was Smith’s earlier analysis of AD patients’ PET scans that revealed their distinct pattern of lowered brain metabolism. She determined that specific parts of the temporal and parietal cerebral cortex — memory network areas of the brain where AD’s earliest pathology surfaces— became increasingly sluggish with time.

Provided by Johns Hopkins Medical Institutions

Source: medicalxpress.com

April 23, 2012

According to a new study, the neuron-killing pathology of Alzheimer’s disease (AD), which begins before clinical symptoms appear, requires the presence of both amyloid-beta (a-beta) plaque deposits and elevated levels of an altered protein called p-tau.

Without both, progressive clinical decline associated with AD in cognitively healthy older individuals is “not significantly different from zero,” reports a team of scientists at the University of California, San Diego School of Medicine in the April 23 online issue of the Archives of Neurology.

"I think this is the biggest contribution of our work," said Rahul S. Desikan, MD, PhD, research fellow and resident radiologist in the UC San Diego Department of Radiology and first author of the study. "A number of planned clinical trials – and the majority of Alzheimer’s studies – focus predominantly on a-beta. Our results highlight the importance of also looking at p-tau, particularly in trials investigating therapies to remove a-beta. Older, non-demented individuals who have elevated a-beta levels, but normal p-tau levels, may not progress to Alzheimer’s, while older individuals with elevated levels of both will likely develop the disease."

The findings also underscore the importance of p-tau as a target for new approaches to treating patients with conditions ranging from mild cognitive impairment (MCI) to full-blown AD. An estimated 5.4 million Americans have AD. It’s believed that 10 to 20 percent of Americans age 65 and older have MCI, a risk factor for AD. Some current therapies appear to delay clinical AD onset, but the disease remains irreversible and incurable.

"It may be that a-beta initiates the Alzheimer’s cascade," said Desikan. "But once started, the neurodegenerative mechanism may become independent of a-beta, with p-tau and other proteins playing a bigger role in the downstream degenerative cascade. If that’s the case, prevention with anti-a-beta compounds may prove efficacious against AD for older, non-demented individuals who have not yet developed tau pathology. But novel, tau-targeting therapies may help the millions of individuals who already suffer from mild cognitive impairment or Alzheimer’s disease." 

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ScienceDaily (Mar. 26, 2012) — Repeated stress triggers the production and accumulation of insoluble tau protein aggregates inside the brain cells of mice, say researchers at the University of California, San Diego School of Medicine in a new study published in the March 26 Online Early Edition of the Proceedings of the National Academy of Sciences.

Exposing mice to 14 days of repeated stress resulted in an accumulation of insoluble phosphorylated tau protein aggregates in brain cells, visualized in this electron micrograph. (Credit: Image courtesy of Robert Rissman, UC San Diego)

The aggregates are similar to neurofibrillary tangles or NFTs, modified protein structures that are one of the physiological hallmarks of Alzheimer’s disease. Lead author Robert A. Rissman, PhD, assistant professor of neurosciences, said the findings may at least partly explain why clinical studies have found a strong link between people prone to stress and development of sporadic Alzheimer’s disease (AD), which accounts for up to 95 percent of all AD cases in humans.

"In the mouse models, we found that repeated episodes of emotional stress, which has been demonstrated to be comparable to what humans might experience in ordinary life, resulted in the phosphorylation and altered solubility of tau proteins in neurons," Rissman said. "These events are critical in the development of NFT pathology in Alzheimer’s disease."

The effect was most notable in the hippocampus, said Rissman, a region of the brain linked to the formation, organization and storage of memories. In AD patients, the hippocampus is typically the first region of the brain affected by tau pathology and the hardest-hit, with substantial cell death and shrinkage.

Not all forms of stress are equally threatening. In earlier research, Rissman and colleagues reported that acute stress — a single, passing episode — does not result in lasting, debilitating long lasting changes in accumulation of phosphorylated tau. Acute stress-induced modifications in the cell are transient, he said, and on the whole, probably beneficial.

"Acute stress may be useful for brain plasticity and helping to facilitate learning. Chronic stress and continuous activation of stress pathways may lead to pathological changes in stress circuitry. It may be too much of a good thing." As people age, perhaps their neuronal circuits do too, he said, becoming less robust and perhaps less capable of completely rebounding from the effects of stress.

"Age is the primary, known risk factor for Alzheimer’s disease. It may be that as we age, our neurons just aren’t as plastic as they once were and some succumb."

The researchers observed that stress cues impacted two key corticotropin-releasing factor receptors, suggesting a target for potential therapies. Rissman noted drugs already exist and are in human trials (for other conditions) that modulate the activity of these receptors.

"You can’t eliminate stress. We all need to be able to respond at some level to stressful stimuli. The idea is to use an antagonist molecule to reduce the effects of stress upon neurons. The stress system can still respond, but the response in the brain and hippocampus would be toned down so that it doesn’t result in harmful, permanent damage."

The authors dedicate this work to long time mentor and colleague, Dr. Wylie Vale, whose years of pioneering work deciphering and describing the stress system were fundamental to this paper. Vale passed away earlier this year at the age of 70.

Source: Science Daily

March 26, 2012

A meta-analysis of previously published studies found that the ratio of blood plasma amyloid-β (Aβ) peptides Aβ42:Aβ40 was significantly associated with development of Alzheimer disease and dementia, according to a report published Online First by Archives of Neurology.

"Plasma levels of amyloid-β (Aβ) peptides have been a principal focus of the growing literature on blood-based biomarkers, but studies to date have varied in design, assay methods, and sample size, making it difficult to readily interpret the overall data," the authors write as background in the study.

Alain Koyama, S.M., then of Harvard School of Public Health and Brigham and Women’s Hospital, Boston, now with the University of California, San Francisco, and colleagues conducted a meta-analysis of 13 previously published studies to examine the association between plasma amyloid-β and development of dementia, Alzheimer disease (AD) and cognitive decline.

The 13 studies included in the analysis had a total of 10,303 participants, and were published between 1995 and 2011. The studies also included measurement of at least one relevant plasma amyloid-β species (Aβ40, Aβ42, or Aβ42: Aβ40 ratio) and reported an effect estimate for dementia, AD or cognitive decline.

The authors found that lower Aβ42: Aβ40 ratios were significantly associated with development of Alzheimer disease and dementia, with most studies in the analysis reporting similar findings. Plasma levels of Aβ40 and Aβ42 alone, however, were not significantly associated with either outcome.

"In conclusion, despite the limitations of existing research and heterogeneity across the studies considered, this systematic review and meta-analysis suggests that the ratio of plasma Aβ42: Aβ40 may have value in predicting the risk for later development of dementia or AD and merits further investigation."

More information: Arch Neurol. Published online March 26, 2012. doi:10.1001/archneurol.2011.1841

Provided by JAMA and Archives Journals

Source: medicalxpress.com

ScienceDaily (Mar. 23, 2012) — Insulin resistance in the brain precedes and contributes to cognitive decline above and beyond other known causes of Alzheimer’s disease, according to a new study by researchers from the Perelman School of Medicine at the University of Pennsylvania. Insulin is an important hormone in many bodily functions, including the health of brain cells. The team identified extensive abnormalities in the activity of two major signaling pathways for insulin and insulin-like growth factor in non-diabetic people with Alzheimer’s disease. These pathways could be targeted with new or existing medicines to potentially help resensitize the brain to insulin and possibly slow down or even improve cognitive decline.

This is the first study to directly demonstrate that insulin resistance occurs in the brains of people with Alzheimer’s disease. The study is now online in the Journal of Clinical Investigation.

"Our research clearly shows that the brain’s ability to respond to insulin, which is important for normal brain function, is going offline at some point. Insulin in the brain not only modulates glucose uptake, but also promotes the health of brain cells — their growth, survival, remodeling, and normal functioning. We believe that brain insulin resistance may be an important contributor to the cognitive decline associated with Alzheimer’s disease," said senior author, Steven E. Arnold, MD, professor of Psychiatry and Neurology. Arnold is also the director of the Penn Memory Center, a National Institute on Aging-designated Alzheimer’s Disease Core Center. "If we can prevent brain insulin resistance from occurring, or re-sensitize brain cells to insulin with any of the currently available insulin-sensitizing diabetes medicines, we may be able to slow down, prevent, or perhaps even improve cognitive decline.

The risk of developing Alzheimer’s disease is increased by 50 percent in people with diabetes. Type 2 diabetes is due to insulin resistance and accounts for 90 percent of all diabetes. The defining clinical feature of Type 2 diabetes (and Type 1 “juvenile” diabetes) is hyperglycemia — high levels of sugar in the blood — but there is no evidence that the brain in Alzheimer’s is hyperglycemic. Insulin acts differently in the brain than in the rest of the body. Researchers found that insulin resistance of the brain occurs in Alzheimer’s disease independent of whether someone has diabetes, by excluding people with a history of diabetes from this study.

The investigators used samples of postmortem brain tissue from non-diabetics who had died with Alzheimer’s disease, stimulated the tissue with insulin, and measured how much the insulin activated various proteins in the insulin-signaling pathways. There was less insulin activation in Alzheimer’s cases than in tissue from people who had died without brain disease. Other proteins linked to insulin action in the brain were abnormal in Alzheimer’s disease samples. These abnormalities were highly correlated with episodic memory and other cognitive disabilities in the Alzheimer’s disease patients.

In tissue from people with Alzheimer’s disease and mild cognitive impairment (MCI), researchers found that changes to a protein called insulin receptor substrate-1 (IRS-1 pS636/639 and pS616) in brain cells were linked to the severity of memory impairments regardless of age, sex, diabetes history, or apolipoprotein E (APOE) gene status. Levels of IRS-1 were also significantly associated with, but not likely to affect, the presence of amyloid beta plaques and neurofibrillary tangles, the signature markers of Alzheimer’s disease. This suggests that insulin resistance contributes to cognitive decline independent of the classical pathology of Alzheimer’s disease.

Researchers noted that three insulin-sensitizing medicines are already approved by the FDA for treatment of diabetes. These drugs readily cross the blood-brain barrier and may have therapeutic potential to correct insulin resistance in Alzheimer’s disease and MCI. “Clinical trials would need to be conducted to determine the impact the drugs have on Alzheimer’s disease and MCI in non-diabetic patients,” said Dr. Arnold.

Source: Science Daily

March 21, 2012

Researchers at Weill Cornell Medical College have developed a computer program that has tracked the manner in which different forms of dementia spread within a human brain. They say their mathematic model can be used to predict where and approximately when an individual patient’s brain will suffer from the spread, neuron to neuron, of “prion-like” toxic proteins — a process they say underlies all forms of dementia.

Their findings, published in the March 22 issue of Neuron, could help patients and their families confirm a diagnosis of dementia and prepare in advance for future cognitive declines over time. In the future — in an era where targeted drugs against dementia exist — the program might also help physicians identify suitable brain targets for therapeutic intervention, says the study’s lead researcher, Ashish Raj, Ph.D., an assistant professor of computer science in radiology at Weill Cornell Medical College.

"Think of it as a weather radar system, which shows you a video of weather patterns in your area over the next 48 hours," says Dr. Raj. "Our model, when applied to the baseline magnetic resonance imaging scan of an individual brain, can similarly produce a future map of degeneration in that person over the next few years or decades.

"This could allow neurologists to predict what the patient’s neuroanatomic and associated cognitive state will be at any given point in the future. They could tell whether and when the patient will develop speech impediments, memory loss, behavioral peculiarities, and so on," he says. "Knowledge of what the future holds will allow patients to make informed choices regarding their lifestyle and therapeutic interventions.

"At some point we will gain the ability to target and improve the health of specific brain regions and nerve fiber tracts," Dr. Raj says. "At that point, a good prediction of a subject’s future anatomic state can help identify promising target regions for this intervention. Early detection will be key to preventing and managing dementia." 

Tracking the Flow of Proteins

The computational model, which Dr. Raj developed, is the latest, and one of the most significant, validations of the idea that dementia is caused by proteins that spread through the brain along networks of neurons. It extends findings that were widely reported in February that Alzheimer’s disease starts in a particular brain region, but spreads further via misfolded, toxic “tau” proteins. Those studies, by researchers at Columbia University Medical Center and Massachusetts General Hospital, were conducted in mouse models and focused only on Alzheimer’s disease.

In this study, Dr. Raj details how he developed the mathematical model of the flow of toxic proteins, and then demonstrates that it correctly predicted the patterns of degeneration that results in a number of different forms of dementia.

He says his model is predicated on the recent understanding that all known forms of dementia are accompanied by, and likely caused by, abnormal or “misfolded” proteins. Proteins have a defined shape, depending on their specific function — but proteins that become misshapen can produce unwanted toxic effects. One example is tau, which is found in a misfolded state in the brains of both Alzheimer’s patients and patients with frontal temporal dementia (FTD). Other proteins, such as TDP43 and ubiquitin, are also found in FTD, and alpha synuclein is found in Parkinson’s disease.

These proteins are called “prion-like” because misfolded, or diseased, proteins induce the misfolding of other proteins they touch down a specific neuronal pathway. Prion diseases (such as mad cow disease) that involve transmission of misfolded proteins are thought to be infectious between people. “There is no evidence that Alzheimer’s or other dementias are contagious in that way, which is why their transmission is called prion-like.”

Simple Explanation for Clinically Observed Patterns of Dementia

Dr. Raj calls his model of trans-neuronal spread of misfolded proteins “very simple.” It models the same process by which any gas diffuses in air, except that in the case of dementias the diffusion process occurs along connected neural fiber tracts in the brain.

"This is a common process by which any disease-causing protein can result in a variety of dementias," he says.

The model identifies the neural sub-networks in the brain into which misfolded proteins will collect before moving on to other brain areas that are connected by networks of neurons. In the process the proteins alter normal functioning of all brain areas they visit.

"What is new and really quite remarkable is the network diffusion model itself, which acts on the normal brain connectivity network and manages to reproduce many known aspects of whole brain disease patterns in dementias," Dr. Raj says. "This provides a very simple explanation for why different dementias appear to target specific areas of the brain."

In the study, he was able to match patterns from the diffusion model, which traced protein disbursal in a healthy brain, to the patterns of brain atrophy observed in patients with either Alzheimer’s disease or FTD. This degeneration was measured using MRI and other tools that could quantify the amount of brain volume loss experienced in each region of the patient’s brain. Co-author Amy Kuceyeski, Ph.D., a postdoctoral fellow who works with Dr. Raj, helped analyze brain volume measurements in the diseased brains.

"Our study demonstrates that such a spreading mechanism leads directly to the observed patterns of atrophy one sees in various dementias," Dr. Raj says. "While the classic patterns of dementia are well known, this is the first model to relate brain network properties to the patterns and explain them in a deterministic and predictive manner."

Provided by New York- Presbyterian Hospital

Source: medicalxpress.com

March 21, 2012

Alzheimer’s disease and other forms of dementia may spread within nerve networks in the brain by moving directly between connected neurons, instead of in other ways proposed by scientists, such as by propagating in all directions, according to researchers who report the finding in the March 22 edition of the journal Neuron.

Led by neurologist and MacArthur Foundation “genius award” recipient William Seeley, MD, from the UCSF Memory and Aging Center, and post-doctoral fellow Helen Juan Zhou, PhD, now a faculty member at Duke-NUS Graduate Medical School in Singapore, the researchers concluded that a nerve region’s connectedness to a disease hot spot trumps overall connectedness, spatial proximity and loss of growth-factor support in predicting its vulnerability to the spread of disease in some of the most common forms of dementia, including Alzheimer’s disease.

The finding, based on new magnetic resonance imaging research (MRI), raises hopes that physicians may be able to use MRI to predict the course of dementias – depending on where within an affected network degenerative damage is first discovered – and that researchers may use these predicted outcomes to determine whether a new treatment is working. Network modeling combined with functional MRI might serve as an intermediate biomarker to gauge drug efficacy in clinical trials before behavioral changes become measurable, according to Seeley.

"Our next goal is to further develop methods to predict disease progression, using these models to create a template for how disease will progress in the brain of an affected individual," Seeley said. "Already this work suggests that if we know the wiring diagram in a healthy brain, we can predict where the disease is going to go next. Once we can predict how the network will change over time we can predict how the patient’s behavior will change over time and we can monitor whether a potential therapy is working."

The new evidence suggests that different kinds of dementias spread from neuron to neuron in similar ways, even though they act on different brain networks, according to Seeley. Seeley’s previous work and earlier clinical and anatomical studies showed that the patterns of damage in the dementias are linked to particular networks of nerve cells, but until now scientists have found it difficult to evaluate in humans their ideas about how this neurodegeneration occurs.

In the current study, the researchers modeled not only the normal nerve network that can be affected by Alzheimer’s disease, but also those networks affected by frontotemporal dementia (FTD) and related disorders, a class of degenerative brain diseases identified by their devastating impact on social behaviors or language skills.

The scientists mapped brain connectedness in 12 healthy people. Then they used data from patients with the five different diseases to map and compare specific regions within the networks that are damaged by the different dementias.

"For each dementia, we looked at four ideas that scientists often bring up to explain how dementia might target brain networks," Seeley said. "The different proposed mechanisms lead to different predictions about how a region’s place in the healthy network affects its vulnerability to disease."

In the “nodal stress” hypothesis, small regions within the brain that serve as hubs to carry heavy signaling traffic would undergo wear and tear that gives rise to or worsens disease. In the “trophic failure” mechanism, breakdowns in connectivity would disrupt transport through the network of growth factors needed to maintain neurons. In the “shared vulnerability” mechanism, specific genes or proteins common to neurons in a network would make them more susceptible to disease. But predictions from the “trans-neuronal spread” mechanism model best fit the network connectivity maps constructed by the researchers.

"The trans-neuronal spread model predicts that the more closely connected a region is to the node of disease onset – which we call the epicenter – then the more vulnerable that region will be once the disease begins to spread," Seeley said. "It’s as if the disease is emanating from a point of origin, but it can reach any given target faster if there is a stronger connection."

The scientists tracked and analyzed linkages within nerve networks that the dementias target. They used a technique called functional connectivity MRI to measure and spatially represent activity in specific regions of key networks in the brains of the healthy subjects. The MRI readout allowed the researchers to model each region within the network as a distinct but interconnected node. They ranked the nodes that most consistently fired together as being the most closely connected.

Across the five diseases investigated in the study, trans-neuronal spread was the proposed mechanism for which the data best matched the predictions. Previous studies of animals and cells in the laboratory also support the idea that disease-related proteins can spread from an affected neuron to other neurons via intercellular connections.

For more than three decades researchers have been noticing that regions affected by Alzheimer’s disease are connected by axons that branch between and connect neurons, Seeley said. Trans-neuronal spread is a proven hallmark of certain rare neurodegenerative diseases – such as Creutzfeldt-Jakob disease – that are propagated by misfolded cell-surface proteins called prions, which induce neighboring proteins to change shape, aggregate and wreak havoc.

While Alzheimer’s disease and FTD are not considered infectious, abnormal protein structures also are implicated in these common dementias. Recent experiments in which researchers transplanted post-mortem, human brain extracts from dementia patients into genetically modified mice have resulted in disease, Seeley said, “But it is difficult to explore these ideas in humans, and we wanted to begin to bridge this knowledge gap.”

Provided by University of California - San Francisco

Source: medicalxpress.com 

ScienceDaily (Mar. 13, 2012) — A compound that previously progressed to Phase II clinical trials for cancer treatment slows neurological damage and improves brain function in an animal model of Alzheimer’s disease, according to a new study. The study published the week of March 13 in the Journal of Neuroscience shows that the compound epothilone D (EpoD) is effective in preventing further neurological damage and improving cognitive performance in a mouse model of Alzheimer’s disease (AD). The results establish how the drug might be used in early-stage AD patients.

This is an electron micrographic picture of a cross section of a nerve from an Alzheimer’s model mouse. Structural abnormalities in the nerve are indicated by the arrows. Alzheimer model mice that received the drug epothilone D had a significant reduction in the number of these abnormalities. (Credit: Zhang, et al. The Journal of Neuroscience 2012.)

Investigators from the Perelman School of Medicine at the University of Pennsylvania, led by first author Bin Zhang, MD, PhD, senior research investigator, and senior author Kurt R. Brunden, PhD, Director of Drug Discovery at the Center for Neurodegenerative Disease Research (CNDR), administered EpoD to aged mice that had memory deficits and inclusions within their brains that resemble the tangles formed by misfolded tau protein, a hallmark of AD. In nerve cells, tau normally stabilizes structures called microtubules, the molecular railroad tracks upon which cellular cargo is transported. Tangles may compromise microtubule stability, with resulting damage to nerve cells. A drug that could increase microtubule stability might improve nerve-cell function in AD and other diseases where tangles form in the brain.

EpoD acts by the same microtubule-stabilizing mechanism as the FDA-approved cancer drug paclitaxel (Taxol™). These drugs prevent cancer cell proliferation by over-stabilizing specialized microtubules involved in the separation of chromosomes during the process of cell division. However, the Penn researchers previously demonstrated that EpoD, unlike paclitaxel, readily enters the brain and so may be useful for treating AD and related disorders.

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ScienceDaily (Mar. 6, 2012) — A team of academic researchers has identified the intracellular mechanisms regulated by vitamin D3 that may help the body clear the brain of amyloid beta, the main component of plaques associated with Alzheimer’s disease.

Published in the March 6 issue of the Journal of Alzheimer’s Disease, the early findings show that vitamin D3 may activate key genes and cellular signaling networks to help stimulate the immune system to clear the amyloid-beta protein.

Previous laboratory work by the team demonstrated that specific types of immune cells in Alzheimer’s patients may respond to therapy with vitamin D3 and curcumin, a chemical found in turmeric spice, by stimulating the innate immune system to clear amyloid beta. But the researchers didn’t know how it worked.

"This new study helped clarify the key mechanisms involved, which will help us better understand the usefulness of vitamin D3 and curcumin as possible therapies for Alzheimer’s disease," said study author Dr. Milan Fiala, a researcher at the David Geffen School of Medicine at UCLA and the Veterans Affairs Greater Los Angeles Healthcare System.

For the study, scientists drew blood samples from Alzheimer’s patients and healthy controls and then isolated critical immune cells from the blood called macrophages, which are responsible for gobbling up amyloid beta and other waste products in the brain and body.

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