Ohio State implants first brain pacemaker to treat Alzheimer's

COLUMBUS, Ohio – During a five-hour surgery last October at The Ohio State University Wexner Medical Center, Kathy Sanford became the first Alzheimer's patient in the United States to have a pacemaker implanted in her brain.

She is the first of up to 10 patients who will be enrolled in an FDA-approved study at Ohio State's Wexner Medical Center to determine if using a brain pacemaker can improve cognitive and behavioral functioning in patients with Alzheimer's disease.

The study employs the use of deep brain stimulation (DBS), the same technology used to successfully treat about 100,000 patients worldwide with movement disorders such as Parkinson's disease. In the study, researchers hope to determine whether DBS surgery can improve function governed by the frontal lobe and neural networks involved in cognition and behavior by stimulating certain areas of the brain with a pacemaker.

Dr. Douglas Scharre, neurologist and director of the division of cognitive neurology, and Dr. Ali Rezai, neurosurgeon and director of the neuroscience program, both at Wexner Medical Center, are conducting the study.

“If the early findings that we're seeing continue to be robust and progressive, then I think that will be very promising and encouraging for us,” says Rezai, who also directs the Center for Neuromodulation at Ohio State. “But so far we are cautiously optimistic."

The deep brain stimulation implant is similar to a cardiac pacemaker device with the exception that the pacemaker wires are implanted in the brain rather than the heart.

“Basically, the pacemakers send tiny signals into the brain that regulate the abnormal activity of the brain and normalize it more,” says Rezai. “Right now, from what we're seeing in our first patient, I think the results are encouraging, but this is research. We need to do more research and understand what's going on."

The study, which will enroll people with mild or early-stage Alzheimer's disease, will help determine if DBS has the potential to improve cognitive, behavioral and functional deficits.

Sanford continues to be evaluated to determine the effectiveness of the technology, says Rezai. She says she volunteered for the study to help others avoid the angst she has suffered as Alzheimer's slowly disrupted her life.

“I'm just trying to make the world a better place,” says Sanford. “That's all I'm doing."

Her father, Joe Jester, says he is proud that his daughter is participating in the study, and is pleased to see her showing improvements.

“This study seemed to just give us hope,” said Jester. “I guess we were at the place where you just don't do anything and watch the condition deteriorate over the years, or try to do something that would give us hope and might stop the progression of this disease."

Alzheimer's disease is the most common form of degenerative dementia, afflicting about 5.5 million Americans and costing more than $100 billion per year, ranking it the third costliest disease in terms of health care expenditures in the United States.

Alzheimer's disease – which has no cure and is not easily managed – becomes progressively disabling with loss of memory, cognition, worsening behavioral function, in addition to a gradual loss of independent functioning, says Scharre.

The Ohio State neurology team is nationally renowned for expertise in dementia and Alzheimer's care and research. In addition, the neuromodulation team at Ohio State are pioneers in the use of DBS to treat Parkinson's disease, as well as exploring the use of DBS for other neurological and neurobehavioral conditions. Researchers at the Neuromodulation Center are completing a study of DBS in patients with traumatic brain injuries, and have initiated a study of DBS for treating obesity.

The Alzheimer's study is scheduled to be completed in 2015. (Source: EurekAlert! A service of AAAS and Ohio State Wexner Medical Center).

Major step toward an Alzheimer's vaccine

This press release is available in French

Quebec City, January 15, 2013—A team of researchers from Université Laval, CHU de Québec, and pharmaceutical firm GlaxoSmithKline (GSK) has discovered a way to stimulate the brain's natural defense mechanisms in people with Alzheimer's disease. This major breakthrough, details of which are presented today in an early online edition of the Proceedings of the National Academy of Sciences (PNAS), opens the door to the development of a treatment for Alzheimer's disease and a vaccine to prevent the illness.

One of the main characteristics of Alzheimer's disease is the production in the brain of a toxic molecule known as amyloid beta. Microglial cells, the nervous system's defenders, are unable to eliminate this substance, which forms deposits called senile plaques.

The team led by Dr. Serge Rivest, professor at Université Laval's Faculty of Medicine and researcher at the CHU de Québec research center, identified a molecule that stimulates the activity of the brain's immune cells. The molecule, known as MPL (monophosphoryl lipid A), has been used extensively as a vaccine adjuvant by GSK for many years, and its safety is well established.

In mice with Alzheimer's symptoms, weekly injections of MPL over a twelve-week period eliminated up to 80% of senile plaques. In addition, tests measuring the mice's ability to learn new tasks showed significant improvement in cognitive function over the same period.

The researchers see two potential uses for MPL. It could be administered by intramuscular injection to people with Alzheimer's disease to slow the progression of the illness. It could also be incorporated into a vaccine designed to stimulate the production of antibodies against amyloid beta. “The vaccine could be given to people who already have the disease to stimulate their natural immunity,” said Serge Rivest. “It could also be administered as a preventive measure to people with risk factors for Alzheimer's disease."

“When our team started working on Alzheimer's disease a decade ago, our goal was to develop better treatment for Alzheimer's patients,” explained Professor Rivest. “With the discovery announced today, I think we're close to our objective."(Source: EurekAlert! A service of AAAS and Université Laval).

Right target, but missing the bulls-eye for Alzheimer's

UCLA researchers discover new point of attack for drug therapy

Alzheimer's disease is the most common cause of late-life dementia. The disorder is thought to be caused by a protein known as amyloid-beta, or Abeta, which clumps together in the brain, forming plaques that are thought to destroy neurons. This destruction starts early, too, and can presage clinical signs of the disease by up to 20 years.

For decades now, researchers have been trying, with limited success, to develop drugs that prevent this clumping. Such drugs require a “target” — a structure they can bind to, thereby preventing the toxic actions of Abeta.

Now, a new study out of UCLA suggests that while researchers may have the right target in Abeta, they may be missing the bull's-eye. Reporting in the Jan. 23 issue of the Journal of Molecular Biology, UCLA neurology professor David Teplow and colleagues focused on a particular segment of a toxic form of Abeta and discovered a unique hairpin-like structure that facilitates clumping.

“Every 68 seconds, someone in this country is diagnosed with Alzheimer's,” said Teplow, the study's senior author and principal investigator of the NIH-sponsored Alzheimer's Disease Research Center at UCLA. “Alzheimer's disease is the only one of the top 10 causes of death in America that cannot be prevented, cured or even slowed down once it begins. Most of the drugs that have been developed have either failed or only provide modest improvement of the symptoms. So finding a better pathway for these potential therapeutics is critical."

The Abeta protein is composed of a sequence of amino acids, much like “a pearl necklace composed of 20 different combinations of different colors of pearl,” Teplow said. One form of Abeta, Abeta40, has 40 amino acids, while a second form, Abeta42, has two extra amino acids at one end.

Abeta42 has long been thought to be the toxic form of Abeta, but until now, no one has understood how the simple addition of two amino acids made it so much more toxic then Abeta40.

In his lab, Teplow and his colleagues used computer simulations in which they looked at the structure of the Abeta proteins in a virtual world. The researchers first created a virtual Abeta peptide that only contained the last 12 amino acids of the entire 42–amino-acid-long Abeta42 protein. Then, said Teplow, “we just let the molecule move around in a virtual world, letting the laws of physics determine how each atom of the peptide was attracted to or repulsed by other atoms."

By taking thousands of snapshots of the various molecular structures the peptides created, the researchers determined which structures formed more frequently than others. From those, they then physically created mutant Abeta peptides using chemical synthesis.

“We studied these mutant peptides and found that the structure that made Abeta42 Abeta42 was a hairpin-like turn at the very end of the peptide of the whole Abeta protein,” Teplow said.

The hairpin turn structure was not previously known in the detail revealed by the researchers, “so we feel our experiments were novel,” he said. “Our lab is the first to show that it is this specific turn that accounts for the special ability of Abeta42 to aggregate into clumps that we think kills neurons. Abeta40, the Abeta protein with two less amino acids at the end of the protein, did not do the same thing."

Hopefully, the work of the Teplow laboratory presents what may the most relevant target yet for the development of drugs to fight Alzheimer's disease, the researchers said. (Source: EurekAlert! A service of AAAS and the University of California-Los Angeles).

Neurons die in Alzheimer's because of faulty cell cycle control before plaques and tangles appear

Research presented at ASCB annual meeting, Dec. 15-19, San Francisco

The two infamous proteins, amyloid-beta (Aβ) and tau, that characterize advanced Alzheimer's disease (AD), start healthy neurons on the road to cell death long before the appearance of the deadly plaques and tangles by working together to reactivate the supposedly blocked cell cycle in brain cells, according to research presented on Dec. 17 at the American Society for Cell Biology's Annual Meeting in San Francisco.

Working in a mouse model of AD, George Bloom, PhD, of the University of Virginia (UVA) reports that neurons in AD start dying because they break the first law of human neuronal safety – stay out of the cell cycle.

Most normal adult neurons are permanently postmitotic; that is, they have finished dividing and are locked out of the cell cycle. In contrast, AD neurons frequently re-enter the cell cycle but fail to complete mitosis, and ultimately die. By considering this novel perspective on AD as a problem of the cell cycle, Dr. Bloom and colleagues at UVA and at the University of Alabama, Birmingham, have discovered what they call an “ironic pathway” to neuronal cell death. The process requires the coordinated action of both Aβ and tau, which are the building blocks of plaques and tangles, respectively. Dr. Bloom's results show just how toxic the two proteins can be even when free in solution and not aggregated into plaques and tangles.

Using mouse neurons grown in culture, the UVA researchers found that Aβ oligomers, which are small aggregates of just a few Aβ molecules each, induce the neurons to re-enter the cell cycle. Interestingly, the neurons must make and accumulate tau in order for this cell cycle re-entry to occur. The mechanism for this misplaced re-entry into the cell cycle requires that Aβ oligomers activate multiple protein kinase enzymes, each of which must then attach a phosphate to a specific site on the tau protein.

Following up on the cell culture results, Dr. Bloom and colleagues confirmed that Aβ-induced, tau-dependent cell cycle re-entry occurs in the brains of mice that were genetically engineered to mimic brains with human AD. The mouse brains were found to accumulate massive numbers of neurons that had transitioned from a permanent cell cycle stop, known as G0 (G zero), to G1, the first stage of the cell cycle, by the time they were 6 months old. Remarkably, otherwise identical mice that lacked functional tau genes showed no sign of cell cycle re-entry, confirming the cell culture results.

Neuronal cell cycle re-entry, a key step in the development of AD, can therefore be caused by signaling from Aβ through tau. Thus, Aβ and tau co-conspire to trigger seminal events in AD pathogenesis independently of their incorporation into plaques and tangles. Most important, Dr. Bloom believes that the activated protein kinases and phosphorylated forms of tau identified in this study represent potential targets for early diagnosis and treatment of AD. (Source: EurekAlert! A service of AAAS and the American Society for Cell Biology).

Alzheimer's patients with non-spousal caregivers are less likely to participate in clinical trials

PHILADELPHIA - People with Alzheimer's disease are less likely to participate in a clinical trial if they have non-spouse caregivers, according to a study by a team of researchers including the Perelman School of Medicine at the University of Pennsylvania. The new study, published in the December 19th, 2012, issue of Neurology®, the medical journal of the American Academy of Neurology, demonstrates that additional recruitment and retention strategies may be required to increase enrollment of AD patients with caregivers other than spouses.

Alzheimer's trials - which require both the patient with Alzheimer's and a reliable study partner to enroll together - often struggle to recruit enough patients. In this study, two-thirds of Alzheimer's clinical trial participants were accompanied by their spouse, in contrast to the national average showing that 68 percent of people with Alzheimer's primarily receive care from their children, children-in-law or grandchildren. The study also found that AD participants with a study partner who was neither a spouse nor an adult child were more likely to drop out before the study completed. In addition, these participants were more likely to suffer a serious adverse event during the trial.

“The majority of Alzheimer's patients are cared for by caregivers who are not their spouses, but we discovered that in Alzheimer's disease clinical trials, most patients' caregivers are their spouses,” said senior study author Jason Karlawish, MD, co-director of the Penn Memory Center and professor of Medicine, Medical Ethics and Health Policy in the Perelman School of Medicine at the University of Pennsylvania. “This result is a call to action. Nonspousal caregivers and the patients they care for represent an untapped opportunity to increase recruitment into Alzheimer's clinical trials and to assure that the research results reflect the broad community of patients and their caregivers."

The study also found variations in demographics that may be relevant to clinical trial designs. For example, only five percent of participants across the trial were Hispanic and those with an adult child study partner were twice as likely as those with spouse partners to be Hispanic. In addition, six percent of participants were African-American and those with adult child study partners were nearly three times as likely to be African-American as those with spouse study partners. And, while the ratio of men and women with Alzheimer's disease was similar, the majority of study partners/caregivers were female. (Source: EurekAlert! A service of AAAS and the University of Pennsylvania School of Medicine).

Scientists establish link between inflammatory process and progression of Alzheimer's disease

Drugs targeting IL-1 beta production may benefit Alzheimer's patients

WORCESTER, MA — An international team of researchers from the University of Massachusetts Medical School, the University of Bonn and the Center for Advanced European Studies and Research in Germany have shown that a well-known immune and inflammatory process plays an important role in the pathology of Alzheimer's disease. This process, which results in the mature production of the pro-inflammatory cytokine called interleukin-1 beta (IL-1B) and is involved in the body's defense against infection, has also been established as a clinical target for rheumatoid arthritis. The finding, published in Nature, points to the possibility that drugs that disrupt the production of IL-1B, such as those for rheumatoid arthritis, may also prove beneficial for patients with Alzheimer's.

“This finding represents an important new clinical target for patients with Alzheimer's disease,” said Douglas T. Golenbock, MD, chief of infectious diseases and immunology and professor of medicine and microbiology & physiological systems. “We've known for years that the plaques associated with Alzheimer's were surrounded by microglia, the resident immune cell of the central nervous system. What we didn't know was what role, if any, inflammation played in the progression of the disease. With this link we have a new path to potentially identifying and attacking this horrible disease."

The most common form of dementia, Alzheimer's is a degenerative neurological disorder that leads to memory loss, impaired cognitive function, and eventually death. By 2050 it is predicted that 1 in 85 people will suffer from Alzheimer's disease. There are no available treatments.

A key physiological component of Alzheimer's disease is the presence of extracellular plaques, primarily composed of beta amyloid peptides, which aggregate in the brain. These plaques are believed to be toxic and the chief cause of nearby neuron death and cortical material loss. The hippocampus, which plays an important role in short-term memory, is one of the first regions of the brain to suffer damage from Alzheimer's.

Golenbock and colleagues had established in previous studies that neurons in cell cultures died after nearby microglia cells, the main form of active immune defense in the brain and spinal cord, were exposed to amyloid beta fibrils, such as those found in Alzheimer's plaques. Typically, microglias are responsible for removing plaques, damaged neurons and infectious agents from the central nervous system. The beta amyloid peptide, however, generates inflammation in the central nervous system by activating microglia to produce neurotoxic compounds, including cytokines. How this process was being activated in patients with Alzheimer's disease, though, was unclear.

Earlier work done in the Golenbock laboratory demonstrated that beta amyloid peptide could induce the production of IL-1B by activating a multi-protein receptor complex in microglial cells known as the NLRP3 inflammasome. Because of its ability to sense the beta amyloid peptide, the NLRP3 inflammasome has been implicated in several chronic inflammatory diseases, including gout and asbestosis. Examining Alzheimer's tissue samples, scientists found that “every one of the cell samples contained increased evidence of activated inflammasomes, strongly suggesting that they were producing IL-1B,” said Golenbock.

“Taken together with our earlier studies, this strongly suggested a role for NLRP3 and caspase-1 in producing IL-1B leading to Alzheimer's disease progression,” Golenbock said.

To assess the precise impact of NLRP3 and caspase-1 on Alzheimer's disease in an organism, researchers recorded cognitive function and memory in mice models that expressed genes associated with familial Alzheimer's but that were deficient in NLRP3 or caspase-1, and compared them with Alzheimer's mice that had otherwise intact immune systems. When researchers performed memory recall tests of the Alzheimer's in NLRP3- or caspase-1- mutant mice, they found the animals exhibited far better memory recall and appeared protected from memory loss. However, Alzheimer's mice that expressed NLRP3 and caspase-1 at normal levels exhibited symptoms consistent with Alzheimer's disease. Further examination revealed that NLRP3 and caspase-1 deficient mice showed a decrease in beta amyloid plaques and in increased ability of the microglia to remove fibrillar beta amyloid from the brain.

It was also revealed that activated IL-1 levels in the NLRP3 and caspase-1deficient mice were reduced compared to symptom-bearing counterparts. Because of NLRP3 and caspase-1 deficits, these mice produced less IL-1. These deficits appeared to promote formation of a microglia cell phenotype which was more capable of metabolizing and removing Alzheimer's plaques from the central nervous system.

“These findings suggest that a knockout of NLRP3, caspase-1 or mature IL-1B may represent a novel therapeutic intervention for Alzheimer's disease,” said Golenbock. “It's possible that drugs that block NLRP3 or IL-1B – including some of which are already in clinical trials or on the market – might provide some benefit,” said Golenbock.

“The critical part, though, is how much NLRP3 or IL-1B production can these drugs disrupt,” said Golenbock. “I believe that it's not enough to block just 90 percent; it will probably have to be closer to 100 percent.” (Source: EurekAlert! A service of AAAS and the University of Massachusetts Medical School).

Alzheimer's Disease: Inflammation as a new therapeutic approach

Researchers discover a signal switch which protects against loss of function of nerve cells

The number of Alzheimer's patients will continue to dramatically increase in the next several decades. Various teams of researchers worldwide are feverishly investigating precisely how the illness develops. A team of scientists under the guidance of the University of Bonn and University of Massachusetts (USA) and with the participation of the German Center for Neurodegenerative Diseases have discovered a new signaling pathway in mice which is involved in the development of chronic inflammation which causes nerve cells in the brain to malfunction and die off. The results are now being published in the renowned scientific journal “Nature".

Alzheimer's disease gradually leads to the destruction of nerve cells and thus to significant losses in memory formation and recall. “Many years before the initial symptoms occur, so-called plaques, which consist of incorrectly folded beta-amyloid peptides, form in the brain of affected persons,” says lead author Prof. Dr. Michael T. Heneka, director of the Clinical Neurosciences study group at the Neurology Clinic of the University of Bonn and researcher at the German Center for Neurodegenerative Diseases (DZNE). In addition, there are abnormal tau protein deposits in the brain cells of the patients. “As a result of a signal cascade, there is a chronic inflammatory reaction and the progressive loss of nerve cells,” reports Prof. Dr. Eicke Latz from the Institute of Innate Immunity of the Bonn University Hospital, who also performs research for the DZNE and the University of Massachusetts Medical School (USA).

Caspase-1 is increased in the brains of Alzheimer's patients

The scientists from the University of Bonn and the DZNE, in a successful alliance of neurologists and immunologists together with their colleagues from the Caesar Research Center and the Technical University of Braunschweig, have discovered a new signaling pathway which is involved in the development of chronic inflammation of the brain cells. Caspase-1 plays a key role and it is jointly responsible for the activation of the inflammatory reaction. The researchers detected substantially increased amounts of caspase-1 in the brains of Alzheimer's patients in comparison to healthy persons. These increased levels were associated with chronic inflammatory reactions of the immune cells in the brain. The scientists also observed these findings in genetically modified mice who represent a well established model of Alzheimer's disease.

Silent genes prevent inflammation and memory loss

The gene NLRP3 is also crucially involved in the inflammatory signaling pathways which lead to the degneration and loss of brain cells. The scientists therefore deactivated the NLRP3 gene as well as caspase-1 in the Alzheimer's mice. As a result, there was no inflammation in the brains of these animals and they did not develop any memory loss. In addition, there was shown to be far less beta-amyloid peptide deposited in the brain cells of the genetically silent mice. It is evident that the non-inflamed cells were able to dispose of the deposited plaques much better as “metabolic waste.” If the genes for caspase-1 and NLRP3 are muted, the nerve cells and memory are evidently protected from the typical Alzheimer's processes.

Possible starting point for new therapies

These results indicate a starting point which could possibly aid in the development of new forms of therapy for the treatment of early-stage Alzheimer's disease. “We are still in the basic research stage and thus therapeutic success cannot be foreseen at this time point,” says Prof. Heneka. “There is still a long way to go until the first clinical studies.” (Source: EurekAlert! A service of AAAS and the University of Bonn).

Risk genes for Alzheimer's and mental illness linked to brain changes at birth

CHAPEL HILL, N.C. – Some brain changes that are found in adults with common gene variants linked to disorders such as Alzheimer's disease, schizophrenia, and autism can also be seen in the brain scans of newborns.

“These results suggest that prenatal brain development may be a very important influence on psychiatric risk later in life,” said Rebecca C. Knickmeyer, PhD, lead author of the study and assistant professor of psychiatry in the University of North Carolina School of Medicine. The study was published by the journal Cerebral Cortex on Jan. 3, 2013.

The study included 272 infants who received MRI scans at UNC Hospitals shortly after birth. The DNA of each was tested for 10 common variations in 7 genes that have been linked to brain structure in adults. These genes have also been implicated in conditions such as schizophrenia, bipolar disorder, autism, Alzheimer's disease, anxiety disorders and depression.

For some polymorphisms – such as a variation in the APOE gene which is associated with Alzheimer's disease – the brain changes in infants looked very similar to brain changes found in adults with the same variants, Knickmeyer said. “This could stimulate an exciting new line of research focused on preventing onset of illness through very early intervention in at-risk individuals."

But this was not true for every polymorphism included in the study, said John H. Gilmore, MD, senior author of the study and Thad & Alice Eure Distinguished Professor and Vice Chair for Research and Scientific Affairs in the UNC Department of Psychiatry.

For example, the study included two variants in the DISC1 gene. For one of these variants, known as rs821616, the infant brains looked very similar to the brains of adults with this variant. But there was no such similarity between infant brains and adult brains for the other variant, rs6675281.

“This suggests that the brain changes associated with this gene variant aren't present at birth but develop later in life, perhaps during puberty,” Gilmore said.

“It's fascinating that different variants in the same gene have such unique effects in terms of when they affect brain development,” said Knickmeyer. (Source: EurekAlert! A service of AAAS and University of North Carolina Health Care).

Promising compound restores memory loss and reverses symptoms of Alzheimer's

New research in the FASEB Journal by NIH scientists suggests that a small molecule called TFP5 rescues plaques and tangles by blocking an overactive brain signal, thereby restoring memory in mice with Alzheimer's

A new ray of hope has broken through the clouded outcomes associated with Alzheimer's disease. A new research report published in January 2013 print issue of the FASEB Journal by scientists from the National Institutes of Health shows that when a molecule called TFP5 is injected into mice with disease that is the equivalent of human Alzheimer's, symptoms are reversed and memory is restored—without obvious toxic side effects.

“We hope that clinical trial studies in AD patients should yield an extended and a better quality of life as observed in mice upon TFP5 treatment,” said Harish C. Pant, Ph.D., a senior researcher involved in the work from the Laboratory of Neurochemistry at the National Institute of Neurological Disorders at Stroke at the National Institutes of Health in Bethesda, MD. “Therefore, we suggest that TFP5 should be an effective therapeutic compound."

To make this discovery, Pant and colleagues used mice with a disease considered the equivalent of Alzheimer's. One set of these mice were injected with the small molecule TFP5, while the other was injected with saline as placebo. The mice, after a series of intraperitoneal injections of TFP5, displayed a substantial reduction in the various disease symptoms along with restoration of memory loss. In addition, the mice receiving TFP5 injections experienced no weight loss, neurological stress (anxiety) or signs of toxicity. The disease in the placebo mice, however, progressed normally as expected. TFP5 was derived from the regulator of a key brain enzyme, called Cdk5. The over activation of Cdk5 is implicated in the formation of plaques and tangles, the major hallmark of Alzheimer's disease.

“The next step is to find out if this molecule can have the same effects in people, and if not, to find out which molecule will,” said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal. “Now that we know that we can target the basic molecular defects in Alzheimer's disease, we can hope for treatments far better – and more specific – than anything we have today."(Source: EurekAlert! A service of AAAS and the Federation of American Societies for Experimental Biology).

Detrimental effect of obesity on lesions associated with Alzheimer's disease

In France, more than 860,000 people suffer from Alzheimer's disease and related disorders, making them the largest cause of age-related loss of intellectual function. Cognitive impairments observed in Alzheimer's disease result from the accumulation of abnormal tau proteins in nerve cells undergoing degeneration. We know that obesity, a major risk factor in the development of insulin resistance and type 2 diabetes, increases the risk of dementia during the aging process. However, the effects of obesity on ‘Taupathies' (i.e. tau protein-related disorders), including Alzheimer's disease, were not clearly understood. In particular, researchers assumed that insulin resistance played a major role in terms of the effects of obesity.

The “Alzheimer & Tauopathies” team from mixed research unit 837 (Inserm/Université Lille 2/Université Lille Nord de France) directed by Dr. Luc Buée, in collaboration with mixed research unit 1011 “Nuclear receptors, cardiovascular diseases and diabetes", have just demonstrated, in mice, that obese subjects develop aggravated disorders. To achieve this result, young transgenic mice, who develop tau-related neurodegeneration progressively with age, were put on a high-fat diet for five months, leading to progressive obesity.

“At the end of this diet, the obese mice had developed an aggravated disorder both from the point of view of memory and modifications to the Tau protein” explains David Blum, in charge of research at Inserm.

This study uses a neurodenegeneration model of Alzheimer's disease to provide experimental evidence of the relationship between obesity and disorders linked to the tau protein. Furthermore, it indicates that insulin resistance is not the aggravating factor, as was suggested in previous studies.

“Our research supports the theory that environmental factors contribute massively to the development of this neurodegenerative disorder” underlines the researcher. “Our work is now focussing on identifying the factors responsible for this aggravation” he adds. (Source: EurekAlert! A service of AAAS and the Institut national de la santé et de la recherche médicale).

Transmission of tangles in Alzheimer's mice provides more authentic model of tau pathology

New model provides first step in generating new therapies

PHILADELPHIA – Brain diseases associated with the misformed protein tau, including Alzheimer's disease and frontotemporal lobar degeneration with tau pathologies, are characterized by neurofibrillary tangles (NFTs) comprised of pathological tau filaments. Tau tangles are also found in progressive supranuclear palsy, cortical basal degeneration and other related tauopathies, including chronic traumatic encephalopathy due to repetitive traumatic brain injuries sustained in sports or on the battle field.

By using synthetic fibrils made from pure recombinant protein, Penn researchers provide the first direct and compelling evidence that tau fibrils alone are entirely sufficient to recruit and convert soluble tau within cells into pathological clumps in neurons, followed by transmission of tau pathology to other inter-connected brain regions from a single injection site in an animal model of tau brain disease.

The laboratory of senior author Virginia M.-Y. Lee, Ph.D., MBA, director of the Center for Neurodegenerative Disease Research and professor of Pathology and Laboratory Medicine at the Perelman School of Medicine, University of Pennsylvania, published their findings in the Journal of Neuroscience this week.

“Our new model of tau pathology spread provides an explanation to account for the stereotypical progression of Alzheimer's and other related tauopathies by implicating the cell-to-cell transmission of pathological tau in this process,” says Lee.

Young mice overexpressing mutant human tau were injected with synthetic preformed tau fibrils. These fibrils were assembled from recombinant full-length tau or truncated tau containing four microtubule-binding repeats. The synthetic tau fibrils caused rapid induction of NFT-like inclusions in the brains of the mice. These inclusions then propagated from injected sites to connected brain regions in a dose- and time-dependent manner.

Interestingly, injection of the synthetic tau fibrils into either the hippocampus or the striatum and cortex led to distinctly different patterns of spreading, which is reflective of their functional connectivities. The simplest explanation for this phenomenon is that the injected pathological tau is taken up by the processes of normal neurons where it then corrupts the tau in these nerve cells followed by the transport of the corrupted tau along processes where it is released, taken up by other neurons. Then the cycle repeats itself over and over again, thereby driving disease progression, say the researchers.

What's more, unlike tau pathology that spontaneously develops in older Alzheimer's mice, the inclusions induced by the synthetic tau injections in the younger mice more closely resembled Alzheimer's tangles in their physical and biochemical make-up.

The study demonstrates that synthetic tau fibrils alone are capable of inducing authentic NFT-like tau clumps and initiating spreading of tau pathology in an Alzheimer's mouse model.

The team is now conducting studies to identify monoclonal antibodies for passive immunotherapies related to tau pathologies.

“We are also exploring the mechanisms of spreading and the relationship of tau tangles with senile plaques,” says Lee. “We believe that this newly described transmission model may more faithfully recapitulate human Alzheimer's pathogenesis than the conventional transgenic mouse models of overexpressing mutant genes that develop aggregates. Exploring if this injection-transmission model is more appropriate for the progression of Alzheimer's, as well as Parkinson's, is another priority.” (Source: EurekAlert! A service of AAAS and the University of Pennsylvania School of Medicine).

Feeling lonely linked to increased risk of dementia in later life

But those who live alone not at increased risk, study shows

Feeling lonely, as distinct from being/living alone, is linked to an increased risk of developing dementia in later life, indicates research published online in the Journal of Neurology Neurosurgery and Psychiatry.

Various factors are known to be linked to the development of Alzheimer's disease, including older age, underlying medical conditions, genes, impaired cognition, and depression, say the authors. But the potential impacts of loneliness and social isolation—defined as living alone, not having a partner/spouse, and having few friends and social interactions — have not been studied to any great extent, they say. This is potentially important, given the ageing population and the increasing number of single households, they suggest.

They therefore tracked the long term health and wellbeing of more than 2000 people with no signs of dementia and living independently for three years. All the participants were taking part in the Amsterdam Study of the Elderly (AMSTEL), which is looking at the risk factors for depression, dementia, and higher than expected death rates among the elderly. At the end of this period, the mental health and wellbeing of all participants was assessed using a series of validated tests. They were also quizzed about their physical health, their ability to carry out routine daily tasks, and specifically asked if they felt lonely. Finally, they were formally tested for signs of dementia.

At the start of the monitoring period, around half (46%; 1002) the participants were living alone and half were single or no longer married. Around three out of four said they had no social support. Around one in five (just under 20%; 433) said they felt lonely. Among those who lived alone, around one in 10 (9.3%) had developed dementia after three years compared with one in 20 (5.6%) of those who lived with others. Among those who had never married or were no longer married, similar proportions developed dementia and remained free of the condition.

But among those without social support, one in 20 had developed dementia compared with around one in 10 (11.4%) of those who did have this to fall back on. And when it came to those who said they felt lonely, more than twice as many of them had developed dementia after three years compared with those who did not feel this way (13.4% compared with 5.7%).

Further analysis showed that those who lived alone or who were no longer married were between 70% and 80% more likely to develop dementia than those who lived with others or who were married. And those who said they felt lonely were more than 2.5 times as likely to develop the disease. And this applied equally to both sexes.

When other influential factors were taken into account, those who said they were lonely were still 64% more likely to develop the disease, while other aspects of social isolation had no impact.

“These results suggest that feelings of loneliness independently contribute to the risk of dementia in later life,” write the authors. “Interestingly, the fact that ‘feeling lonely' rather than ‘being alone' was associated with dementia onset suggests that it is not the objective situation, but, rather, the perceived absence of social attachments that increases the risk of cognitive decline,” they add.

They suggest that loneliness may affect cognition and memory as a result of loss of regular use, or that loneliness could itself be a sign of emerging dementia, and either be a behavioural reaction to impaired cognition or a marker of undetected cellular changes in the brain. (Source: EurekAlert! A service of AAAS and British Medical Journal).

Worries about dementia how hospitalization affects the elderly

Older people often worry about dementia and while some risks are known, for example alcoholism or stroke, the effects of illness are less clear. New research published in BioMed Central's open access journal Critical Care looks at illness requiring hospitalization and treatment in the intensive care unit (ICU) and finds that infection or severe sepsis, neurological dysfunction, such as delirium, or acute dialysis are all independently associated with an increased risk of a subsequent diagnosis of dementia.

This study was based on a random 5% of older (66 years or above) Medicare patients who were treated in intensive care in 2005 and whose health was followed for a further three years using Medicare claims data. Of the 25,368 patients included in the study 4,519 (17.8%) went on to receive a diagnosis of dementia during the three year follow up period.

Patients with previous indications of cognitive impairment for whom dementia could have been an escalation of a pre-existing condition were excluded from the study.

Increasing age was very strongly associated with diagnosis of dementia following ICU. The risk at 75 was more than double that of the 66 to 69 year olds. And this rose to more than five times the risk for those age 85 and older. Women had a marginally higher risk than men and, as other studies have shown, race was also important to risk. Length of stay in ICU was not a factor nor was the need for mechanical ventilation.

Three factors related to the critical illness were independently associated with an increased risk of a diagnosis of dementia: a critical illness with the presence of an infection which increased to a higher risk with more severe infection such as severe sepsis, having acute neurologic dysfunction during critical illness, including anoxic brain damage, encephalopathy, and transient mental disorders, and finally acute renal failure requiring dialysis. This last risk was time-dependent and only increased the risk 6 months after the patient had been discharged from hospital.

Dr Hannah Wunsch, from Columbia University Medical Center, lead author of the study commented, “Due to increasing life spans and better hospital care, millions of older people now survive a critical illness every year. Our study provides a greater understanding of the consequences of these hospitalizations on subsequent risk of receiving a diagnosis of dementia, and may allow for better planning and targeting future studies to high risk populations.” (Source: EurekAlert! A service of AAAS and BioMed Central).

Passive smoking increases risk of severe dementia, according to study in China

Study of nearly 6,000 people in 5 provinces in China reveals that people exposed to passive smoking have a significantly increased risk of severe dementia syndromes

Passive smoking, also known as ‘second-hand' smoke or environmental tobacco smoke (ETS), is known to cause serious cardiovascular and respiratory diseases, including coronary heart disease and lung cancer. However, until now it has been uncertain whether ETS increases the risk of dementia, mainly due to lack of research. Previous studies have shown an association between ETS and cognitive impairment, but this is the first to find a significant link with dementia syndromes.

The study, published in Occupational and Environmental Medicine, is a collaboration between scientists at King's College London and Anhui Medical University, China, along with colleagues in the UK and USA.

According to the World Health Organization (WHO), nearly 80 percent of the more than one billion smokers worldwide live in low- and middle-income countries, where the burden of tobacco-related illness and death is heaviest; but only 11 percent of the world's population are protected by comprehensive smoke-free laws.

China is the largest consumer of tobacco in the world, with 350 million smokers. Since 2006, the Chinese government has actively promoted the introduction of smoke-free environments in hospitals, schools, on public transport and in other public places, but implementation has not been widespread.

Recent data show that the prevalence of passive smoking is still high, with over 50 percent of people exposed to environmental tobacco smoke on a daily basis. China also has the highest number of dementia sufferers in the world, with increasing rates of new cases as the population ages.

Dr Ruoling Chen, senior lecturer in public health from King's College London, and colleagues interviewed 5,921 people aged over 60 in the rural and urban communities of Anhui, Guangdong, Heilongjiang, Shanghai and Shanxi to characterise their levels of ETS exposure, smoking habits and assess levels of dementia syndromes.

They found that 10 percent of the group had severe dementia syndromes. This was significantly related to exposure level and duration of passive smoking. The associations with severe syndromes were found in people who had never smoked and in former and current smokers.

The data from the Anhui cohort, which were collected at baseline in 2001-03 for dementia syndromes and in the follow up in 2007-08 for ETS exposure and dementia, further excluded the possibility that dementia syndromes caused people to be more exposed to environmental tobacco smoke.

Dr Ruoling Chen, also a visiting professor at Anhui Medical University said: 'Passive smoking should be considered an important risk factor for severe dementia syndromes, as this study in China shows. Avoiding exposure to ETS may reduce the risk of severe dementia syndromes.

‘China, along with many other countries, now has a significantly ageing population, so dementia has a significant impact not only on the patients but on their families and carers. It's a huge burden on society.'

The findings from this study, together with a second recent study by Chen and colleagues published in Alzheimer's & Dementia on the links between passive smoking and Alzheimer's disease, strengthen the case for public health measures to protect people from exposure to environmental tobacco smoke.

‘At present, we know that about 90 percent of the world's population live in countries without smoke-free public areas. More campaigns against tobacco exposure in the general population will help decrease the risk of severe dementia syndromes and reduce the dementia epidemic worldwide.'

He added: ‘The increased risk of severe dementia syndromes in those exposed to passive smoking is similar to increased risk of coronary heart disease – suggesting that urgent preventive measures should be taken, not just in China but many other countries.' (Source: EurekAlert! A service of AAAS and King’s College of London).

Method developed by VTT targets diagnosis of early Alzheimer's disease

Half of patients could be diagnosed a year earlier than current clinical practice

A software tool called PredictAD developed by VTT Technical Research Centre of Finland promises to enable earlier diagnosis of the disease on the basis of patient measurements and large databases. Alzheimer's disease currently takes on average 20 months to diagnose in Europe. VTT has shown that the new method could allow as many as half of patients to get a diagnosis approximately a year earlier.

VTT has been studying whether patients suffering from memory problems could be diagnosed with Alzheimer's disease at an earlier stage in the light of their measurement values. The study involved processing patient measurements using VTT's PredictAD system, which was developed to support clinical decision-making. The findings were published in the Journal of Alzheimer's Disease in November 2012.

VTT has developed a novel approach for measuring the state of the patient reliably and objectively in cooperation with clinicians of University of Eastern Finland and Copenhagen University Hospital Rigshospitalet. The system compares the patient's measurements with measurements of other patients in large databases and provides an index and a graphical representation reflecting the state of the patient. Modern hospitals have huge data reserves that could be utilised in diagnostics by systematic mathematical modelling. Successful early diagnostics combined with new forms of care may reduce suffering and delay the institutionalisation of patients.

VTT's decision support system and imaging methods developed by VTT and Imperial College London were studied using ADNI material compiled in the United States. The study covered the records of a total of 288 patients suffering from memory problems, 140 of whom were diagnosed with Alzheimer's disease on average 21 months after the initial measurements.

The study showed that half of the patients could have been given a diagnosis of Alzheimer's disease around a year earlier. The accuracy of the predictions was comparable to clinical diagnosis. Treatments designed to slow down the progress of the disease could therefore be started earlier.

Early prediction of the disease is also important from the perspective of drug trials. If patients whose disease is still in the early stages can be included in trials, the treatment can be expected to be more effective.

The method will be tested at several memory clinics in Europe over the next few years. VTT's goal is to expand the method to also cover several other illnesses that cause dementia in addition to Alzheimer's disease. (Source: EurekAlert! A service of AAAS and VTT Technical Research Centre of Finland).