In a series of studies Penn researchers demonstrated that, while tests created for AD are effectively diagnosing the condition when it’s clear cut, additional tests are needed to address the many cases with mixed pathology.
‘With the emergence of disease-modifying treatments for AD and other neurodegenerative diseases, it will be of utmost importance to accurately identify the underlying neuropathology in patients,’ said senior author John Q. Trojanowski, MD, PhD, professor of Pathology and Laboratory Medicine and co-director of the Center for Neurodegenerative Disease Research at Penn.
In one study, the Penn team compared results of a test looking at levels of tau and amyloid beta (Aß) in the spinal fluid, using two different types of analytical platforms. They determined that values from the two platforms could effectively be transformed into equivalent units, and these values accurately distinguished AD from FTLD. A cutoff of 0.34 for the t-tau:Aß1-42 ratio had 90 – 100 percent sensitivity and 91-96.7 percent specificity to differentiate FTLD cases, respectively.
In another study, the team looked at patient cases with more than one underlying neurodegenerative disease and compared the accuracy of the biomarkers using clinical and neuropathological diagnosis. They determined that cerebral spinal fluid (CSF) Aß and tau assays provided a valid diagnosis of AD but, in mixed pathology cases where Alzheimer’s was present along with other diseases (confirmed by autopsy), the testing strategies classified the diagnosis as AD alone.
‘We need to develop better CSF diagnostic panels for the early diagnosis of neurodegenerative dementias, including those due to mixed neurodegenerative disease pathologies that commonly co-occur with Alzheimer’s,’ said senior author Murray Grossman, MD, professor of Neurology and director of the Penn FTLD Center. Perelman School of Medicine

Dr James Flanagan, a Breast Cancer Campaign scientific fellow in the Department of Surgery and Cancer at Imperial College London, has uncovered the first strong evidence that molecular or ‘epigenetic’ changes in a gene can be associated with breast cancer risk and can be detected many years before breast cancer develops.
The research involved 640 women with breast cancer and 741 controls who enrolled in three previous studies, the earliest of which began in 1992. The researchers analysed blood samples that the women donated on average three years before being diagnosed with breast cancer to find out whether the alteration of single genes by a process called methylation can predict whether women have an increased breast cancer risk.
Dr Flanagan found that the women with the highest level of methylation on one area of a gene called ATM were twice as likely to get breast cancer as women with the lowest level. This result was particularly clear in blood samples taken from women under the age of 60.
Importantly, because this is the first study using blood taken on average three years before diagnosis and in some cases up to eleven years, it shows that the genes were not altered because of active cancer in the body or by treatments for cancer, which has been a problem with previous studies that took blood after diagnosis.
These findings provide strong evidence that looking at this type of epigenetic alteration (methylation) on individual genes could be used as a blood test to help assess breast cancer risk. When used in combination with other risk assessment tools such as genetic testing and risk factor profiling, this simple blood test could identify those at higher risk, helping doctors to monitor and one day maybe even prevent breast cancer ever developing.
The findings now need rigorous testing in many more individuals and many more genes that contribute to a person’s risk profile need to be identified, as this is just one gene that makes up a small component.
Epigenetics research is changing the way scientists think about genes and their development and so could play an important role in helping to prevent cancer. It was previously thought that only errors in the fundamental genetic information from our DNA – whether inherited or caused by environmental factors – determined whether our cells become cancerous. However, new research is showing how chemical modifications to DNA, that control our genes, could be even more important than our DNA alone in determining how our cells grow. Imperial College London

Transposon-mediated insertional mutagenesis accelerates the progression of ductal pancreatic cancer in mice.
In a study researchers have identified a potential new therapeutic target for pancreatic cancer.
The team found that when a gene involved in protein degradation is switched-off through chemical tags on the DNA’s surface, pancreatic cancer cells are protected from the bodies’ natural cell death processes, become more aggressive, and can rapidly spread.
Pancreatic cancer kills around 8,000 people every year in the UK and, although survival rates are gradually improving, fewer than 1 in 5 patients survive for a year or more following their diagnosis.
Co-lead author Professor David Tuveson, from Cancer Research UK’s Cambridge Research Institute, said: ‘The genetics of pancreatic cancer has already been studied in some detail, so we were surprised to find that this gene hadn’t been picked up before. We suspected that the fault wasn’t in the genetic code at all, but in the chemical tags on the surface of the DNA that switch genes on and off, and by running more lab tests we were able to confirm this.’
The team expects this gene, USP9X, could be faulty in up to 15 per cent of pancreatic cancers, raising the prospect that existing drugs, which strip away these chemical tags, could be an effective way of treating some pancreatic cancers.
.’ This study strengthens our emerging understanding that we must also look into the biology of cells to identify all the genes that play a role in cancer. ‘
…’Drugs which strip away these tags are already showing promise in lung cancer and this study suggests they could also be effective in treating up to 15 per cent of pancreatic cancers,’ continues Professor Tuveson.
The researchers used a mouse model of pancreatic cancer to screen for genes that speed up pancreatic cancer growth using a technique called ‘Sleeping Beauty transposon mutagenesis’. This system uses mobile genetic elements that hop around the cell’s DNA from one location to the next. Cells that acquire mutations in genes that contribute to cancer development will grow out and ‘driver’ cancer genes may be identified.
By introducing the Sleeping Beauty transposon into mice pre-disposed to develop pancreatic cancer, the researchers were able to screen for a class of genes called a tumour suppressor that, under normal circumstances, would protect against cancer. These genes are a bit like the cell’s ‘brakes’, so when they become faulty there is little to stop the cell from multiplying out of control.
This approach uncovered many genes already linked to pancreatic cancer. But unexpectedly, USP9X, was identified. Wellcome Trust Sanger Institute

Researchers studying multiple sclerosis (MS) have long been looking for the specific molecules in the body that cause lesions in myelin, the fatty, insulating cells that sheathe the nerves. Nearly a decade ago, a group at Mayo Clinic found a new enzyme, called Kallikrein 6, that is present in abundance in MS lesions and blood samples and is associated with inflammation and demyelination in other neurodegenerative diseases. In a study the same group found that an antibody that neutralises Kallikrein 6 is capable of staving off MS in mice.
‘We were able to slow the course of disease through early chronic stages, both in the brain and spinal cord,’ says lead author Isobel Scarisbrick, Ph.D., of the Mayo Clinic Department of Physical Medicine and Rehabilitation.
Researchers looked at mice representing a viral model of MS. The model is based on the theory that infection with viral infection early in life results in an eventual abnormal immune response in the brain and spinal cord. One week after being infected with a virus, the mice showed elevated levels of Kallikrein 6 enzyme in the brain and spinal cord. However, when researchers treated mice to produce an antibody capable of blocking and neutralising the enzyme, they saw a decrease in diseases effecting the brain and spinal cord, including demyelination. The Kallikrein 6 neutralising antibody had reduced inflammatory white blood cells and slowed the depletion of myelin basic protein, a key component of the myelin sheath.
The findings in the MS model have implications for other conditions affecting the brain and spinal cord. The group has previously shown that the Kallikrein 6 enzyme, produced by immune cells, is elevated in spinal cord injury, while other studies have shown it to be elevated in animal models of stroke and patients with post-polio syndrome.
‘These findings suggest Kallikrein 6 plays a role in the inflammatory and demyelinating processes that accompany many types of neurological conditions,’ says Dr. Scarisbrick. ‘In the early chronic stages of some neurological diseases, Kallikrein 6 may represent a good molecule to target with drugs capable of neutralizing its effects.’ Mayo Clinic

A study of almost 3,800 pregnancies has provided the most accurate and direct evidence to date that malaria infection reduces early foetal growth. Low birth weight is the most important risk factor for neonatal mortality in developing countries. The research highlights the importance of preventing malaria in pregnancy.
According to the World Malaria Report 2011, malaria killed an estimated 655,000 people in 2010. The disease is one of the most common parasitic infections to affect pregnancy. Previous studies have suggested that infection with both P. falciparum and P. vivax malaria during pregnancy reduces birth weight whether or not maternal symptoms are present. However, these studies have been hampered by difficulties in estimating gestational age accurately and diagnosing malaria infection in early pregnancy.
Now researchers at the Shoklo Malaria Research Unit on the border of Thailand and Myanmar, part of the Wellcome Trust-Mahidol University-Oxford University Tropical Medicine Research Programme, have used ultrasound scans to provide the first direct evidence of the effect of malaria on foetal growth in pregnancy. Antenatal ultrasound, which is essential for dating pregnancy accurately, is becoming more widely available in developing countries. The technology also allows the diameter of the foetus’s head to be measured. For infections that occur in early pregnancy, the researchers believe that the size of the head may be the most appropriate indicator of growth restriction.
The ultrasound scans revealed that the diameter of the average foetus’s head was significantly smaller when malaria infection occurred in the first half of pregnancy when compared to pregnancies unaffected by malaria. On average, at the mid-pregnancy ultrasound scan the foetuses’ heads were 2% smaller when affected by malaria. Even a single infection of treated P. falciparum or P. vivax malaria was associated with reduced foetal head diameter, irrespective of whether the woman had shown symptoms or not.
However, although a single early detected and well-treated malaria episode had an effect on foetal head size at mid-trimester, this was not seen at delivery, suggesting that early treatment with effective drugs may allow for growth to recover later in pregnancy.
Strategies to prevent malaria in pregnancy have focused on the second half of pregnancy, when most of the foetal weight gain takes place, but this works suggests that focus should be on the first trimester too. Pregnant woman need to be educated about the risks of malaria in pregnancy and where possible in areas of high risk, offered preventative medication from early pregnancy onwards.