Scientists at Washington University School of Medicine in St. Louis have helped identify many of the biomarkers for Alzheimer’s disease that could potentially predict which patients will develop the disorder later in life. Now, studying spinal fluid samples and health data from 201 research participants at the Charles F. and Joanne Knight Alzheimer’s Disease Research Center, the researchers have shown the markers are accurate predictors of Alzheimer’s years before symptoms develop.
‘We wanted to see if one marker was better than the other in predicting which of our participants would get cognitive impairment and when they would get it,’ said Catherine Roe, PhD, research assistant professor of neurology. ‘We found no differences in the accuracy of the biomarkers.’
The researchers evaluated markers such as the buildup of amyloid plaques in the brain, newly visible thanks to an imaging agent developed in the last decade; levels of various proteins in the cerebrospinal fluid, such as the amyloid fragments that are the principal ingredient of brain plaques; and the ratios of one protein to another in the cerebrospinal fluid, such as different forms of the brain cell structural protein tau.
The markers were studied in volunteers whose ages ranged from 45 to 88. On average, the data available on study participants spanned four years, with the longest recorded over 7.5 years.
The researchers found that all of the markers were equally good at identifying subjects who were likely to develop cognitive problems and at predicting how soon they would become noticeably impaired.
Next, the scientists paired the biomarkers data with demographic information, testing to see if sex, age, race, education and other factors could improve their predictions.
‘Sex, age and race all helped to predict who would develop cognitive impairment,’ Roe said. ‘Older participants, men and African Americans were more likely to become cognitively impaired than those who were younger, female and Caucasian.’
Roe described the findings as providing more evidence that scientists can detect Alzheimer’s disease years before memory loss and cognitive decline become apparent.
‘We can better predict future cognitive impairment when we combine biomarkers with patient characteristics,’ she said. ‘Knowing how accurate biomarkers are is important if we are going to some day be able to treat Alzheimer’s before symptoms and slow or prevent the disease.’
Clinical trials are already underway at Washington University and elsewhere to determine if treatments prior to symptoms can prevent or delay inherited forms of Alzheimer’s disease. Reliable biomarkers for Alzheimer’s should one day make it possible to test the most successful treatments in the much more common sporadic forms of Alzheimer’s. Washington University School of Medicine

In laboratory studies, scientists at the Johns Hopkins Kimmel Cancer Center have developed a way to personalise chemotherapy drug selection for cancer patients by using cell lines created from their own tumors.
If the technique is successful in further studies, it could replace current laboratory tests to optimise drug selection that have proven technically challenging, of limited use, and slow, the researchers say.
Oncologists typically choose anticancer drugs based on the affected organs’ location and/or the appearance and activity of cancer cells when viewed under a microscope. Some companies offer commercial tests on surgically removed tumours using a small number of anticancer drugs. But Anirban Maitra, MBBS, professor of pathology and oncology at the Johns Hopkins University School of Medicine, says the tissue samples used in such tests may have been injured by anaesthetic drugs or shipping to a lab, compromising test results.
By contrast, he says ‘our cell lines better and more accurately represent the tumours, and can be tested against any drug library in the world to see if the cancer is responsive.’
The Johns Hopkins scientists developed their test-worthy cell lines by injecting human pancreatic and ovarian tumour cells into mice genetically engineered to favour tumour growth. Once tumours grew to one centimetre in diameter in the mice, the scientists transferred the tumours to culture flasks for additional studies and tests with anticancer drugs.
In one experiment, they successfully pinpointed the two anticancer drugs from among more than 3,000 that were the most effective in killing cells in one of the pancreatic cancer cell lines
The new method was designed to overcome one of the central problems of growing human tumour cell lines in a laboratory dish — namely the tendency of non-cancerous cells in a tumour to overgrow cancerous ones, says James Eshleman, M.D., Ph.D., professor of pathology and oncology and associate director of the Molecular Diagnostics Laboratory at Johns Hopkins. As a consequence, it has not been possible to conventionally grow cell lines for some cancers. Still other cell lines, Eshleman says, don’t reflect the full spectrum of disease.
To solve the problem of overcrowding by non-cancerous cells, Maitra and Eshleman bred genetically engineered mice that replace the non-cancerous cells with mouse cells that can be destroyed by chemicals, leaving pure human tumour cells for study.
‘Our technique allows us to produce cell lines where they don’t now exist, where more lines are needed, or where there is a particularly rare or biologically distinctive patient we want to study,’ says Eshleman. John Hopkin’s Hospital

A study led by researchers at the Max Planck Florida Institute for Neuroscience, the first and only U.S. extension of the prestigious Max Planck Society, may hold a breakthrough in the fight to treat Alzheimer’s disease. The study potentially identifies a cause of Alzheimer’s disease—based on a newly-discovered signalling pathway in cellular models of Alzheimer’s disease—and opens the door for new treatments by successfully blocking this pathway. The Institute, which recently opened in December 2012, focuses solely on basic neuroscience research that aims to analyse, map, and decode the human brain—the most important and least understood organ in the body.
‘This study transforms our understanding of the direct cause of Alzheimer’s disease,’ said Principal Investigator Dr. Ryohei Yasuda. ‘With further research, we may open up an entirely new avenue for treatments to combat this disease.’
The scientific community so far has widely accepted that Alzheimer’s disease is caused by the accumulation of a peptide called Amyloid beta. When Amyloid beta is applied to neurons, neuronal morphology becomes abnormal and synaptic function is impaired. However, how Amyloid beta causes dysfunction is unknown. The MPFI research indicates that the presence of Amyloid beta triggers increased levels of a signalling protein, called centaurin-1 (CentA1), that appears to cause neuronal dysfunction – a potentially groundbreaking discovery that uncovers an important intermediary step in the progression of the disease.
As part of the research, the scientists were able to identify CentA1 and measure its negative effects on neurons. Utilising an RNA silencing technique, they turned down the cellular production of CentA1, and showed that affected neurons, exposed to Amyloid beta and exhibiting Alzheimer’s related symptoms, returned to normal morphology and synaptic function, even with the continued presence of Amyloid beta. They further found that increased CentA1 activates a series of proteins, and these proteins form a signalling pathway from CentA1 to neuronal dysfunction. Thus, inhibiting other proteins in the pathway also ‘cured’ affected neurons.
The initial tests reported were conducted on rat brain slices. MPFI has already started to expand their studies to mouse models of Alzheimer’s disease and preliminary experiments show promising results. Ultimately, targeting the components of this newly identified signalling pathway has the potential to open the door for new pharmacological and gene therapies in treatment of Alzheimer’s disease. Dr. Yasuda also anecdotally reports that the effects of CentA1 knock down were observed to be sustained over several weeks and an avenue for future study will be to examine how long the positive effects on neurons are sustained which may indicate the potential impact of treatments derived from this research. EurekAlert

Using a novel method of analysing genetic variations in families, researchers at Johns Hopkins have found that individually harmless genetic variations affecting related biochemical processes may team up to increase the risk of schizophrenia. They say their findings bring some clarity to the murky relationship between genetics and schizophrenia, and may lead to a genetic test that can predict which medications will be effective for individual patients.
‘It’s long been clear that schizophrenia runs in families, but schizophrenia as a simple inherited disease didn’t make sense from an evolutionary point of view because people with the disease tend to have fewer children and the disease-causing genetic variants shouldn’t survive,’ says Dimitri Avramopoulos, M.D., Ph.D., an associate professor of psychiatry in the McKusick-Nathans Institute of Genetic Medicine. Moreover, he says, studies searching for schizophrenia-linked gene variants have found only weak connections to a few genes — nothing that would explain the persistent prevalence of the disease, which affects about 1 percent of the population.
Most geneticists believe that the culprit in so-called complex genetic diseases such as schizophrenia is not just one genetic variant, but more than one acting in concert. It’s also likely that individual cases of the disease are caused by different combinations of variants, Avramopoulos says. He and fellow researchers took this hypothesis a step further, theorising that while our bodies can usually compensate for one faulty gene that affects a particular system, more than one hit to the same system is likely to tip people toward disease.
The research team devised a technique for analysing gene-sequencing data that explores whether variants cluster in a subset of cases in a non-random way. After finding support for their hypothesis in previously obtained data on 123 families with at least two schizophrenia-affected members, they decided to sequence genes connected through a biochemical chain reaction that has been linked to the disease in 48 inpatients. Known as the neuregulin signalling pathway, that chain reaction relays signals within the nervous system.
As they had predicted, the researchers found that some of the families had multiple neuregulin signalling-related variants while others had none, a distribution that was highly unlikely to result from chance. Moreover, the schizophrenia patients with neuregulin signalling variants experienced more hallucinations but less impairment than the other schizophrenia patients in the study.
‘These results support the idea that there’s no single genetic recipe for schizophrenia, but that a build-up of mutations in a pathway related to the disease — like neuregulin signalling — can be the culprit,’ Avramopoulos says. ‘The results are also evidence for the current theory that schizophrenia isn’t a single disease at all, but a suite of related disorders.’ Those patients in the study who did not have neuregulin signalling-related variants likely carried variants in a different pathway instead, he notes.
While the results of the study were surprisingly clear-cut given the small number of families in the study, Avramopoulos cautions that larger studies are needed to confirm the results before drawing any firm conclusions. He also plans to study the exact roles of the schizophrenia-linked variants the team identified. Finally, the encouraging results mean it would be worthwhile to apply the new analytic method to other common diseases, such as diabetes and heart disease, which also appear to have complex genetic roots. John Hopkins University School of Medicine

Some of the dramatic differences seen among patients with schizophrenia may be explained by a single gene that regulates a group of other schizophrenia risk genes.
The study revealed that people with schizophrenia who had a particular version of the microRNA-137 gene (or MIR137), tended to develop the illness at a younger age and had distinct brain features – both associated with poorer outcomes – compared to patients who did not have this version. This work was led by Drs. Aristotle Voineskos and James Kennedy.
Treating schizophrenia is particularly challenging as the illness can vary from patient to patient. Some individuals stay hospitalised for years, while others respond well to treatment.
‘What’s exciting about this study is that we could have a legitimate answer as to why some of these differences occur,’ explained Dr. Voineskos, a clinician-scientist in CAMH’s Campbell Family Mental Health Research Institute. ‘In the future, we might have the capability of using this gene to tell us about prognosis and how a person might respond to treatment.’
‘Drs. Voineskos and Kennedy’s findings are very important as they provide new insights into the genetic basis of this condition that affects thousands of Canadians and their families,’ says Dr. Anthony Phillips, Scientific Director at the Canadian Institutes of Health Research Institute of Neurosciences, Mental Health and Addiction.
Also, until now, sex has been the strongest predictor of the age at which schizophrenia develops in individuals. Typically, women tend to develop the illness a few years later than men, and experience a milder form of the disease.
‘We showed that this gene has a bigger effect on age-at-onset than one’s gender has,’ said Dr. Voineskos, who heads the Kimel Family Translational Imaging-Genetics Research Laboratory at CAMH. ‘This may be a paradigm shift for the field.’
The researchers studied MIR137 — a gene involved in turning on and off other schizophrenia-related genes — in 510 individuals living with schizophrenia. The scientists found that patients with a specific version of the gene tended to develop the illness at a younger age, around 20.8 years of age, compared to 23.4 years of age among those without this version.
‘Although three years of difference in age-at-onset may not seem large, those years are important in the final development of brain circuits in the young adult,’ said Dr. Kennedy, Director of CAMH’s Neuroscience Research Department. ‘This can have major impact on disease outcome.’
In a separate part of the study involving 213 people, the researchers used magnetic resonance brain imaging (MRI) and diffusion tensor-MRI (DT-MRI). They found that individuals with the particular gene version tended to have unique brain features. These features included a smaller hippocampus, which is a brain structure involved in memory, and larger lateral ventricles, which are fluid-filled structures associated with disease outcome. As well, these patients tended to have more impairment in white matter tracts, which are structures connecting brain regions, that serve as the information highways of the brain.
Developing tests that screen for versions of this gene could be helpful in treating patients earlier and more effectively.
‘We’re hoping that in the near future we can use this combination of genetics and brain imaging to predict how severe a version of illness someone might have,’ said Dr. Voineskos. ‘This would allow us to plan earlier for specific treatments and clinical service delivery and pursue more personalised treatment options right from the start.’
This research was funded by the Canadian Institutes of Health Research, the Brain & Behavior Research Foundation and the Ontario Mental Health Foundation. Centre for Addiction and Mental Health (CAMH)