People who are dementia-free but have two parents with Alzheimer’s disease may show signs of the disease on brain scans decades before symptoms appear, according to a new study. ‘Studies show that by the time people come in for a diagnosis, there may be a large amount of irreversible brain damage already present,’ said study author Lisa Mosconi, PhD, with the New York University School of Medicine in New York. ‘This is why it is ideal that we find signs of the disease in high-risk people before symptoms occur.’ For the study, 52 people between the ages of 32 and 72 and free of dementia underwent several kinds of brain scans, including Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) scans. PET scans measure the amount of brain plaques as well as overall brain activity, such as brain metabolism. MRI scans look at brain structure and possible reductions in brain volume. Participants were split into four groups of 13 people: those with a mother with Alzheimer’s disease, a father, both parents, or no family history of the disease. People with both parents who had Alzheimer’s disease showed more severe abnormalities in brain volume, metabolism and five to 10 percent increased brain plaques in certain brain regions compared to the other three groups. ‘Our study also suggests that there might be genes that predispose individuals to develop brain Alzheimer’s pathology as a function of whether one parent or both parents have the disease,’ Mosconi said. ‘We do not yet know which genes, if any, are responsible for these early changes, and we hope that our study will be helpful to future genetic investigations.’ People whose mother had Alzheimer’s disease showed a greater level of the Alzheimer’s disease biomarkers in the brain than people whose father had the disease, which is consistent with previous studies showing that people whose mothers had the disease were more likely to develop it than those with fathers with the disease, Mosconi said. She noted the small sample size of the study. The research was supported by the National Institutes of Health and the Alzheimer’s Association. American Academy of Neurology

A study, carried out on mice, has just confirmed the neurobiological origin of attention-deficit disorder (ADD), a syndrome whose causes are poorly understood. Researchers from CNRS, the University of Strasbourg and INSERM have identified a cerebral structure, the superior colliculus, where hyperstimulation causes behaviour modifications similar to those of some patients who suffer from ADD. Their work also shows noradrenaline accumulation in the affected area, shedding light on this chemical mediator having a role in attention disorders.

Attention-deficit disorder affects between 4-8% of children. It manifests mainly through disturbed attention and verbal and motor impulsiveness, sometimes accompanied by hyperactivity. About 60% of these children still show symptoms in adulthood. No cure exists at this time. The only effective treatment is to administer psychostimulants, but these have substantial side effects, such as dependence. Persistent controversy surrounding the neurobiological origin of this disorder has hindered the development of new treatments.
The study in Strasbourg investigated the behaviour of transgenic mice having developmental defects in the superior colliculus. This structure, located in the midbrain, is a sensory hub involved in controlling attention and visual and spatial orientation. The mice studied were characterised by duplicated neuron projections between the superior colliculus and the retina. This anomaly causes visual hyperstimulation and excess noradrenaline in the superior colliculus. The effects of the neurotransmitter noradrenaline, which vary from species to species, are still poorly understood. However, we do know that this noradrenaline imbalance is associated with significant behavioural changes in mice carrying the genetic mutation. By studying them, researchers have observed a loss of inhibition: for example mice hesitate less to penetrate a hostile environment. They have difficulties in understanding relevant information and demonstrate a form of impulsiveness. These symptoms remind us of adult patients suffering from one of the forms of ADD.
Currently, the fundamental work on ADD uses mainly animal models obtained by mutations that disturb dopamine production and transmission pathways. In mice with a malformed superior colliculus, these pathways are intact. The changes occur elsewhere in the neural networks of the midbrain. By broadening the classic boundary used to research its causes, using these new models would allow a more global approach to ADD to be developed. Characterizing the effects of noradrenaline on the superior colliculus more precisely could open the way to innovative therapeutic strategies. INSERM

People from around the country and the world turn to Johan Van Hove, MD, PhD, for advice on a rare metabolic disease known as NKH, which can disrupt the body in devastating and even deadly ways. Now, Van Hove, a University of Colorado medical school professor, has identified a new disease related to NKH, a finding that resolves previously baffling cases including the death of a Colorado girl.
‘This opens the door,’ Van Hove said. ‘I am hopeful that it will eventually lead to major advances in dealing with these diseases.’ The research team led by Van Hove, including scientists from the United States and five other countries, calls the new disease variant NKH.
The discovery is part of the new wave of personalised medicine being pioneered at CU and other institutions, in which researchers and doctors delve into the human genome to determine what is causing disease and use the information to try to fix the problem.
Van Hove has been on the trail of NKH for 22 years. Much of the funding for his research comes from families and others who have encountered the disease.
NKH, short for non-ketotic hyperglycinaemia, occurs in about one in 60,000 births. It involves the amino acid glycine, a building block for many functions including movement and brain activity. When a genetic mutation prevents the body from breaking down excess glycine, it can cause brain problems including severe epilepsy and impaired intellectual development.
Scientists know the symptoms of NKH and also the genes that, when they malfunction, cause it. But a few patients worldwide had symptoms or glycine test results that were similar but did not quite match up.
One of those patients was a Colorado girl. She seemed fine until she was six months old. Then she began to lose muscle tone. She lost some control of her head movements. Seizures came next, along with a range of muscle twitches. By eight she lost her ability to walk. At the end, she spent most of her time curled in the foetal position.
Several years ago, at age 11, she died.
Researchers kept her genetic material, as they did with other patients who seemed to fall outside the NKH symptoms or who had molecular test results that were outside of the NKH pattern. The patients, some of whom are living, were scattered around the globe, in Australia, Lebanon, Canada and other countries as well as in the United States.
By looking into the genomes of this group of 11, Van Hove and his colleagues found that eight shared a genetic glitch different than the ones associated with NKH.
In other words, ‘this is a new disease,’ said Van Hove, who practices at Children’s Hospital Colorado.
More testing is likely to reveal more such patients and, he said, may allow development of a new drug to make life better for patients with variant NKH. EurekAlert

An international team led by researchers at the Broad Institute and Massachusetts General Hospital (MGH) has identified mutations in a gene that can reduce the risk of developing type 2 diabetes, even in people who have risk factors such as obesity and old age. The results focus the search for developing novel therapeutic strategies for type 2 diabetes; if a drug can be developed that mimics the protective effect of these mutations, it could open up new ways of preventing this devastating disease.
The current study breaks new ground in type 2 diabetes research and guides future therapeutic development in this disease. In the new study, researchers describe the genetic analysis of 150,000 patients showing that rare mutations in a gene called SLC30A8 reduce risk of type 2 diabetes by 65 percent. The results were seen in patients from multiple ethnic groups, suggesting that a drug that mimics the effect of these mutations might have broad utility around the globe. The protein encoded by SLC30A8 had previously been shown to play an important role in the insulin-secreting beta cells of the pancreas, and a common variant in that gene was known to slightly influence the risk of type 2 diabetes. However, it was previously unclear whether inhibiting or activating the protein would be the best strategy for reducing disease risk — and how large an effect could be expected.

‘This work underscores that human genetics is not just a tool for understanding biology: it can also powerfully inform drug discovery by addressing one of the most challenging and important questions — knowing which targets to go after,’ said co-senior author David Altshuler, deputy director and chief academic officer at the Broad Institute and a Harvard Medical School professor at Massachusetts General Hospital.

The use of human genetics to identify protective mutations holds great potential. Mutations in a gene called CCR5 were found to protect against infection with HIV, the virus that causes AIDS; drugs have been developed that block the CCR5 protein. A similar protective association for heart disease set off a race to discover new cholesterol-lowering drugs when mutations in the gene PCSK9 were found to lower cholesterol levels and heart disease risk. The new type 2 diabetes study suggests that CCR5 and PCSK9 are likely just the beginning but that it will take large numbers of samples and careful sleuthing to find additional genes with similar protective properties.

The study grew out of a research partnership that started in 2009 involving the Broad Institute, Massachusetts General Hospital, Pfizer Inc., and Lund University Diabetes Centre in Sweden, which set out to find mutations that reduce a person’s risk of type 2 diabetes. The research team selected people with severe risk factors for diabetes, such as advanced age and obesity, who never developed the disease and in fact had normal blood sugar levels. They focused on a set of genes previously identified as playing a role in type 2 diabetes and used next-generation sequencing to search for rare mutations.

The team identified a genetic mutation that appeared to abolish function of the SLC30A8 gene and that was enriched in non-diabetic individuals studied in Sweden and Finland. The protection was surprising, because studies in mice had suggested that mutations in SLC30A8 might have the opposite effect — increasing rather than decreasing risk of type 2 diabetes. However, because this particular genetic variation was exceedingly rare outside of Finland, it proved difficult to obtain additional evidence to corroborate the initial discovery by the Broad/MGH/Pfizer Inc./Lund team.

Then, in 2012, these unpublished results were shared with deCODE genetics, who uncovered a second mutation in an Icelandic population that also appeared to abolish function of the gene SLC30A8. That mutation independently reduced risk for type 2 diabetes and also lowered blood sugar in non-diabetics without any evident negative consequences.

‘This discovery underscores what can be accomplished when human genetics experts on both sides of the Atlantic come together to apply their craft to founder populations, enabling us to find rare mutations with large effects on disease risk,’ said Kari Stefannson, CEO of deCODE genetics.

Finally, the team set out to ask if the effects of SLC30A8 protective mutations were limited to the two mutations found in populations in Finland and Iceland. As part of the NIH-funded T2D-GENES Project, chaired by Mike Boehnke at the University of Michigan, the Broad Institute had performed sequencing of 13,000 samples drawn from multiple ethnicities. The T2D-GENES Project joined the collaboration, found ten more mutations in the same gene, and again saw a protective effect. Combining all the results confirmed that inheriting one copy of a defective version of SLC30A8 led to a 65 percent reduction in risk of diabetes.

‘Through this partnership, we have been able to identify genetic mutations related to loss of gene function, which are protective against type 2 diabetes,’ said Tim Rolph, Vice President and Chief Scientific Officer of Cardiovascular, Metabolic & Endocrine Disease Research at Pfizer Inc. ‘Such genetic associations provide important new insights into the pathogenesis of diabetes, potentially leading to the discovery of drug targets, which may result in a novel medicine.’ Broad Institute

Scientists from Queen Mary University of London have identified a new gene that may influence the timing of puberty, according to new research. More than 4% of adolescents suffer from early or late-onset puberty, which is associated with health problems including obesity, type-2 diabetes, heart disease and cancer. The findings of the study will make diagnosis easier and more efficient, reducing the risk of disease.
Researchers scanned the genomes of seven families experiencing delayed puberty. Their genetic profiles were analysed to identify specific genes that were different in these families, compared to individuals who started puberty normally. The researchers identified 15 candidate genes which were then examined in a further 288 individuals with late-onset puberty.
One gene was found to have common variants in nine families. The gene appears to contribute to the early development of gonadotropin-releasing hormone (GnRH) neurons in the brain. At puberty, a surge of GnRH is released, signalling to the pituitary gland to release further hormones that act on the ovaries and testes, triggering reproductive function (sexual maturation). If development of the GnRH neurons is delayed, the surge of GnRH that initiates these signals is also delayed.
Dr Sasha Howard, lead author and Clinical Research Fellow at Queen Mary University of London, comments: ‘Studies estimate the majority of variation in the timing of puberty is genetically determined, yet this is one of the first genes with major impact to be identified. This is an exciting finding as disturbed GnRH neuron development has never been linked to simple delayed puberty before, and may reveal a new biological pathway in the control of puberty timing.’
The group has also shown that the same gene may be responsible for completely blocking puberty – a condition known as hypogonadotrophic hypogonadism. Queen Mary University of London