More Accurate Diagnosis of Alzheimer’s

ScienceDaily (Apr. 19, 2011) — A new study from the University of Gothenburg, Sweden, shows how analysing spinal fluid can help to detect Alzheimer's disease at an early stage. The researchers behind the study hope that their findings will contribute to a greater international breakthrough for this type of diagnostic method.

It all comes down to biomarkers, substances that are found at abnormally high or low levels in patients who go on to develop Alzheimer's. The most common biomarkers to be identified by the researchers in the spinal fluid of patients with Alzheimer's are proteins and peptides -- short chains of amino acids.

"What's new about our study is that the biomarkers are really good, better than in the past, as the study was carried out extremely carefully with suitable participants via clinical trials and well implemented and controlled laboratory analyses," says docent Johan Svensson, who is working with professor Kaj Blennow's research group at the Sahlgrenska Academy, which has long been involved in researching the development of these biomarkers and advocating their use.

A total of 60 patients who were being investigated for dementia took part in the study, along with 20 healthy controls.

"We measured levels of the biomarkers in the spinal fluid and found that high levels of these substances confirmed the diagnosis of Alzheimer's with a high degree of accuracy compared with levels in healthy controls and patients with other forms of dementia," says Svensson.

"We also saw that patients who hadn't yet met all the clinical criteria for Alzheimer's had similar levels of the biomarkers in their spinal fluid to patients who had developed the disease fully."

The research group therefore concludes that these measurements can also be used to identify Alzheimer's during the early stages of the disease. In such cases, the biomarkers can be used to identify those patients with mild symptoms who are most likely to benefit from treatment.

"If a medication that affects the course of the disease does become available, it will probably be most effective during the early stages, and these biomarkers could be used in the development of such a medication," says Svensson.

The study will be published in the Journal of Alzheimer's Disease.

Four New Genes for Alzheimer's Disease Risk Identified

ScienceDaily (Apr. 4, 2011) — In the largest study of its kind, researchers from a consortium of 44 universities and research institutions in the United States, including Rush University Medical Center, identified four new genes linked to Alzheimer's disease. Each gene individually adds to the risk of having this common form of dementia later in life.

The findings, published in the April issue of Nature Genetics, offer new insight into the underlying causes of Alzheimer's disease.

"This is a major advance in the field thanks to many scientists across the country working together over several years," said Dr. David Bennett, director of the Rush Alzheimer's Disease Center. "These findings add key information needed to understand the causes of Alzheimer's disease and should help in discovering approaches to its treatment and prevention."

In the study, the Alzheimer's Disease Genetics Consortium conducted a genetic analysis of more than 11,000 people with Alzheimer's disease and nearly the same number of elderly people who have no symptoms of dementia.

The Rush Alzheimer's Disease Center contributed clinical and genomic data from more than 1,500 participants in two of its premier cohort studies, the Rush Religious Orders Study and the Rush Memory and Aging Project.

Three other consortia contributed confirming data from additional people, bringing the total number of people analyzed to over 54,000. The consortium also contributed to the identification of a fifth gene reported by other groups of investigators from the United States, the United Kingdom, France, and other European countries.

Until recently, only four genes associated with late-onset Alzheimer's have been confirmed. The gene for apolipoprotein E-e4, APOE-e4, identified over 15 years ago, has the largest effect on risk. Over the past two years, three additional genes have been identified, including CR1, CLU, and BIN1. The present study adds another four -- MS4A, CD2AP, CD33, and EPHA1 -- and contributes to identifying and confirming two other genes, BIN1 and ABCA7, thereby doubling the number of genes known to play a role in Alzheimer's disease.

The identification of new genes associated with Alzheimer's provides major clues about the causes of the disease, information that is critical for drug discovery. Currently available treatments are only marginally effective.

In addition, genetic studies can help researchers understand the pathogenic mechanisms that begin in the brain long before symptoms appear, eventually destroying large parts of the brain and causing the complete loss of cognitive abilities. One primary goal of genetic studies is to help identify who is likely to develop the disease, which will be important when preventive measures become available.

Currently, Alzheimer's genetics researchers are collaborating on an even larger, similar study. The Alzheimer's Association in the U.S. and the Foundation Plan Alzheimer in France have funded the formation of the International Genomics of Alzheimer's Project, whose members met for the first time in November 2010 in Paris.

The present study was supported by the National Institute on Aging (NIA), part of the National Institutes of Health, which includes 29 Alzheimer's Disease Centers, the National Alzheimer's Coordinating Center, the NIA Genetics of Alzheimer's Disease Data Storage Site, the NIA Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease.

Asthma Drug Could Help Control or Treat Alzheimer's Disease

ScienceDaily (Mar. 27, 2011) — A drug used to treat asthma has been shown to help reduce the formation of amyloid beta, a peptide in the brain that is implicated in the development of Alzheimer's disease, according to researchers at Temple University's School of Medicine.

The researchers published their findings in the American Journal of Pathology.

In previous studies, the Temple researchers discovered that 5-lipoxygenase, an enzyme long known to exist in the brain, controls the activation state of gamma secretase, another enzyme that is necessary and responsible for the final production of amyloid beta. When produced in excess, amyloid beta causes neuronal death and forms plaques in the brain. The amount of these amyloid plaques in the brain is used as a measurement of the severity of Alzheimer's.

In their current study, led by Domenico Praticò, an associate professor of pharmacology in Temple's School of Medicine, the researchers tested the drug Zileuton, an inhibitor of 5-lipoxygenase typically used to treat asthma, in a transgenic mouse model of Alzheimer's disease. At the end of the treatment they found that this drug, by blocking the 5-lipoxygenase, reduced gamma secretase's production of amyloid beta and the subsequent build up of amyloid plaques in the brain by more than 50 percent.

Praticò said that gamma secretase is present throughout the body and, despite its role in the development of amyloid plaques, plays a significant role in numerous important functions. Direct inhibitors of gamma secretase are known, he said, but blocking the enzyme completely may cause problems such as the development of cancer. Unlike classical gamma secretase inhibitors, Zileuton only modulates the protein expression levels, which keeps some of its vital functions in tact while blocking many of its bad effects, which in this case is the development of the amyloid plaques.

Praticò and his colleagues have begun working with researchers in Temple's Moulder Center for Drug Discovery Research to create more potent inhibitors that can target 5-lipoxygenase in the brain and increase the ability to reduce amyloid plaque formation and the development of Alzheimer's. Because Zileuton is already FDA approved, it is known that 5-lipoxygenase inhibition is an acceptable target that is not associated with overt toxicity and therefore not harmful to patients. The new drug derivative might be expected to advance to clinical trials relatively easily.

"This drug is already on the market and, most importantly, is already FDA-approved, so you don't need to go through an intense drug discovery process," said Praticò. "So we could quickly begin a clinical trial to determine if there is a new application for this drug against a disease where there is currently nothing."

The study was funded by the National Institutes of Health and the Alzheimer's Association.

Molécula sintética detecta Alzheimer antes que sintomas apareçam

Moléculas sintéticas

Cientistas desenvolveram uma nova técnica capaz de diagnosticar a doença de Alzheimer a partir de amostras de sangue muito antes de os sintomas aparecerem.

A técnica, ainda em estágio preliminar, utiliza moléculas sintéticas para procurar e identificar anticorpos específicos da doença.

Segundo os pesquisadores, o conceito também poderá ser usado no desenvolvimento de biomarcadores específicos para uma série de outras doenças difíceis de diagnosticar, incluindo o Mal de Parkinson e doenças ligadas ao sistema imunológico, como a esclerose múltipla e o lúpus.

Biomarcadores de anticorpos

"Um dos grandes desafios no tratamento de pacientes com Alzheimer é que, uma vez que os sintomas aparecem, é tarde demais. Você não consegue 'destocar' o sino," afirma o Dr. Dwight German, da Universidade Southwestern, nos Estados Unidos.

Se pudermos encontrar uma maneira de detectar a doença em seus estágios iniciais - antes que o comprometimento cognitivo comece - poderíamos ser capazes de estacioná-la com o desenvolvimento de novas estratégias de tratamento."

Como os pacientes com doença de Alzheimer apresentam uma ativação dosistema imunológico e neurodegeneração em várias regiões cerebrais, os cientistas levantaram a hipótese de que pode haver inúmeros anticorpos no soro dos pacientes afetados que são específicos para a doença e que podem servir como biomarcadores.

Biomarcadores de anticorpos têm sido tradicionalmente descobertos usando antígenos - substâncias, como a proteína de um vírus ou bactéria que desencadeia uma resposta imune.

O problema é identificar previamente um anticorpo sem antes saber o antígeno que desencadeia a sua produção.

Peptoides

A novidade do novo estudo está em desafiar a sabedoria convencional e usar moléculas sintéticas (peptoides), em vez de antígenos, para detectar os sinais da doença em amostras de sangue dos pacientes.

Estes peptoides têm várias vantagens: eles podem ser modificados facilmente e podem ser produzidos rapidamente em quantidades relativamente grandes a custos muito baixos.

Os pesquisadores usaram uma biblioteca de vários milhares de peptoides para rastrear amostras de soro de camundongos com sintomas de esclerose múltipla, bem como de camundongos sadios.

Os peptoides que capturaram mais anticorpos das amostras de sangue dos animais foram identificados como agentes potenciais para a captura de moléculas úteis para diagnóstico.

Marco

Os pesquisadores então fizeram o mesmo com amostras de soro de seis pacientes com Alzheimer, seis pacientes com Parkinson e seis pacientes saudáveis.

Foram identificados três peptoides que capturaram seis vezes mais anticorpos nos pacientes com Alzheimer do que no grupo controle saudável ou nos pacientes com Mal de Parkinson.

Em um estudo adicional com 16 indivíduos saudáveis e 10 portadores de Alzheimer em estágio muito precoce da doença, as três moléculas identificaram o Mal de Alzheimer com 90 por cento de precisão.

"Os resultados deste estudo, embora preliminares, mostram um grande potencial para se tornarem um marco no tratamento da doença," disse German.

Potential Way to Protect Neurons in Parkinson's, Alzheimer's, ALS

ScienceDaily (Mar. 14, 2011) — Cell biologists pondering the death of neurons -- brain cells -- have now shown that by eliminating one ingredient from the cellular machinery, they prolonged the life of neurons stressed by a pesticide chemical. The finding identifies a potential therapeutic target to slow changes that lead to neurodegenerative disorders such as Parkinson's and Alzheimer's diseases.

This is an illustration of a healthy neuron. A UT Health Science Center San Antonio study found a protective mechanism for neurons placed under mitochondrial stress.

The researchers, from The University of Texas Health Science Center San Antonio, found that neurons lacking a substance called caspase-2 were better able to withstand pesticide-induced damage to energy centers known as mitochondria.

Master switch

Caspase-2 appears to be a master switch that can trigger either cell death or survival depending on the amount of cellular damage, the team found. Neurons that lacked caspase-2 showed an increase in protective activities, including the efficient breakdown of obsolete or used proteins. This process, called autophagy, delays cell death.

"This research shows, for the first time, that in the absence of caspase-2 neurons increase autophagy to survive," said study co-author Marisa Lopez-Cruzan, Ph.D., investigator in the cellular and structural biology department at the Health Science Center.

Role of energy centers

Evidence suggests that mitochondrial dysfunction plays an important role in neuronal death in conditions such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease) and Huntington's disease.

"Identifying initiators in the cell death process is important for determining therapeutic approaches to provide the maximum protection of neurons during neurodegenerative conditions," said senior author Brian Herman, Ph.D., vice president for research and professor of cellular and structural biology at the Health Science Center.

Young adult mice

The team studied neurons from young adult mice. This was intended to model the early changes that take place in neurodegenerative diseases.

The research is in the March 11 issue of the Journal of Biological Chemistry.

Dr. Lopez-Cruzan, director of Dr. Herman's laboratory, came up with the idea that caspase-2 protects cells from mitochondrial stress. Meenakshi Tiwari, Ph.D., postdoctoral fellow, expanded upon the initial work and is first author of the paper.

The work was supported by the National Institute on Aging and is part of a second National Institutes of Health MERIT award to Dr. Herman.