It only takes one bad apple to spoil the bunch, and the same may be true of certain proteins in the brain. Studies have suggested that just one rogue protein (in this case, a protein that is misfolded or shaped the wrong way) can act as a seed, leading to the misfolding of nearby proteins. According to an NIH-funded study, various forms of these seeds — originating from the same protein — may lead to different patterns of misfolding that result in neurological disorders with unique sets of symptoms.
‘This study has important implications for Parkinson’s disease and other neurodegenerative disorders,’ said National Institute of Neurological Disorders and Stroke (NINDS) Director Story Landis, Ph.D. ‘We know that among patients with Parkinson’s disease, there are variations in the way that the disorder affects the brains. This exciting new research provides a potential explanation for why those differences occur.’
An example of such a protein is alpha-synuclein, which can accumulate in brain cells, causing synucleinopathies, multiple system atrophy, Parkinson’s disease, Parkinson’s disease with dementia (PDD), and dementia with Lewy bodies (DLB). In addition, misfolded proteins other than alpha-synuclein sometimes aggregate, or accumulate, in the same brains. For example, tau protein collects into aggregates called tangles, which are the hallmark of Alzheimer’s disease and are often found in PDD and DLB brains. Findings from this study raise the possibility that different structural shapes, or strains, of alpha-synuclein may contribute to the co-occurrence of synuclein and tau accumulations in PDD or DLB.
In the new study Jing L. Guo, Ph.D., and her colleagues from the University of Pennsylvania Perelman School of Medicine, Philadelphia, wanted to see if different preparations of synthetic alpha-synuclein fibrils would behave differently in neurons that were in a petri dish as well as in mouse brains. They discovered two strains of alpha-synuclein with distinct seeding activity in cultured neurons: while one strain (strain A) resulted in accumulation of alpha-synuclein alone, the other strain (strain B) resulted in accumulations of both alpha-synuclein and tau.
The researchers also injected strain A or strain B into the brains of mice engineered to make large amounts of human tau, and then monitored the formation of alpha-synuclein and tau aggregates at various time points. Mice that received injections of synuclein strain B showed more accumulation of tau — earlier and across more brain regions — compared to mice that received strain A.
The researchers also examined the brains of five patients who had PDD, some of whom also had Alzheimer’s. In this small sample, there was evidence of two different structural forms of alpha-synuclein, one in PDD brains and a distinctly different one in PDD/Alzheimer’s brains, supporting the existence of disease-specific strains of the protein in human diseases.
‘We are just starting to do work with human tissues,’ said Virginia M.Y. Lee, Ph.D., senior author of the study. ‘We are planning to look at the brains of patients who had Parkinson’s disease, PDD, or DLB to see if there are differences in the distribution of alpha-synuclein strains.’
Although the two strains used in this study were created in test tubes, the authors noted that in human brains, where the environment is much more complicated, the chances of forming additional disease-related alpha-synuclein strains may be greater.
‘These different strains not only can convert normal alpha-synuclein into pathological alpha-synuclein within one cell, they also can morph into new strains as they pass from cell to cell, acquiring the ability to serve as a template to damage both normal alpha-synuclein and other proteins,’ said Dr. Lee. ‘So certain strains, but not all strains, can act as templates to influence the development of other pathologies, such as tau tangles.’
She commented, ‘We are just beginning to understand some of these strains and there may be many others. We hope to find a way to identify strains that are relevant to human disease.’ NINDS

New Northwestern Medicine research on the genetics of diabetes could one day help women know their risk for developing gestational diabetes before they become pregnant — and lead to preventive measures to protect the health of offspring.

Gestational diabetes affects 18 percent of pregnancies but usually disappears when a pregnancy is over. Babies born to women with gestational diabetes are typically larger at birth, which can lead to complications during delivery. They are at an increased risk of developing metabolic diseases, such as diabetes, in childhood and adulthood.

This is the first study to suggest differences between the underlying genetic architecture of diabetes in and outside of pregnancy.

Gestational diabetes has been associated with type 2 diabetes, because, during pregnancy, resistance to insulin increases, similar to the effect of weight gain during a lifetime in a non-pregnant state.

But researchers found variants in two genes — HKDC1 and BACE2 — that were associated with measures of glucose and insulin levels of pregnant women but not associated with these measures in the rest of the population, including people with type 2 diabetes.

‘With additional study and verification of these and other risk genes, we could one day have genetic risk profiles to identify individuals at elevated risk for developing gestational diabetes,’ said M. Geoffrey Hayes, first author of the study.

Hayes is an assistant professor of medicine-endocrinology at Northwestern University Feinberg School of Medicine and assistant professor of anthropology at Northwestern’s Weinberg College of Arts and Sciences.

The findings suggest that the roles of the gene HKDC1 in glucose metabolism and BACE2 in insulin secretion are more important during pregnancy versus the non-pregnant state — across all ethnicities studied.

Researchers used DNA and phenotype data of more than 4,000 participants of four different ancestry backgrounds (Hispanic, Thai, Afro-Caribbean and European) from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. HAPO is a multicenter, international study of pregnant women of varied geographic, ethnic and socio-demographic backgrounds.

This study’s findings could one day help pinpoint quantitative genetic traits that predict which women may develop gestational diabetes. North Western University

By analysing DNA in more than 3,000 tumours, scientists led by Li Ding, PhD, at The Genome Institute have identified 127 repeatedly mutated genes that likely drive the growth of a range of cancers in the body. The discovery sets the stage for devising new diagnostic tools and more personalised cancer treatments aimed at the unique genetic changes found in individual tumours.
The research shows that some of the same genes commonly mutated in certain cancers also occur in seemingly unrelated tumours. For example, a gene mutated in 25 percent of leukaemia cases in the study also was found in tumours of the breast, rectum, head and neck, kidney, lung, ovary and uterus.
Based on the findings, the researchers envision that a single test that surveys errors in a swath of cancer genes eventually could become part of the standard diagnostic workup for most cancers. Results of such testing could guide treatment decisions for patients based on the unique genetic signatures of their tumours.
New insights into cancer are possible because of advances in genome sequencing that enable scientists to analyse the DNA of cancer cells on a scale that is much faster and less expensive today than even a few years ago. While earlier genome studies typically have focused on individual tumour types, the current research is one of the first to look across many different types of cancer.
‘This is just the beginning,’ said senior author Li Ding, PhD, of The Genome Institute at Washington University. ‘Many oncologists and scientists have wondered whether it’s possible to come up with a complete list of cancer genes responsible for all human cancers. I think we’re getting closer to that.’
The new research analysed the genes from 3,281 tumours – a collection of cancers of the breast, uterus, head and neck, colon and rectum, bladder, kidney, ovary, lung, brain and blood. In addition to finding common links among genes in different cancers, the researchers also identified a number of mutations exclusive to particular cancer types.
Looking at a large number of tumours across many different cancers gives the researchers the statistical power they need to identify significantly mutated genes. These genetic errors occur frequently in some cancers and rarely in others but are nevertheless thought to be important to cancer growth. The research was conducted as part of The Cancer Genome Atlas Pan-Cancer effort, funded by the National Cancer Institute and the National Human Genome Research Institute, both at the National Institutes of Health (NIH).
While the average number of mutated genes in tumours varied among the cancer types, most tumours had only two to six mutations in genes that drive cancer. This may be one reason why cancer is so common, the researchers said. ‘While cells in the body continually accumulate new mutations over the years, it only takes a few mutations in key driver genes to transform a healthy cell into a cancer cell,’ noted Ding. Washington University School of Medicine at St. Louis

The trajectory of amyloid plaque build-up—clumps of abnormal proteins in the brain linked to Alzheimer’s disease—may serve as a more powerful biomarker for early detection of cognitive decline rather than using the total amount to gauge risk, researchers from Penn Medicine’s Department of Radiology suggest in a new study.
Amyloid plaque that starts to accumulate relatively early in the temporal lobe, compared to other areas and in particular to the frontal lobe, was associated with cognitively declining participants, the study found. ‘Knowing that certain brain abnormality patterns are associated with cognitive performance could have pivotal importance for the early detection and management of Alzheimer’s,’ said senior author Christos Davatzikos, PhD, professor in the Department of Radiology, the Center for Biomedical Image Computing and Analytics, at the Perelman School of Medicine at the University of Pennsylvania.

Today, memory decline and Alzheimer’s—which 5.4 million Americans live with today—is often assessed with a variety of tools, including physical and bio fluid tests and neuroimaging of total amyloid plaque in the brain. Past studies have linked higher amounts of the plaque in dementia-free people with greater risk for developing the disorder. However, it’s more recently been shown that nearly a third of people with plaque on their brains never showed signs of cognitive decline, raising questions about its specific role in the disease.
Now, Dr. Davatzikos and his Penn colleagues, in collaboration with a team led by Susan M. Resnick, PhD, Chief, Laboratory of Behavioral Neuroscience at the National Institute on Aging (NIA), used Pittsburgh compound B (PiB) brain scans from the Baltimore Longitudinal Study of Aging’s Imaging Study and discovered a stronger association between memory decline and spatial patterns of amyloid plaque progression than the total amyloid burden.
‘It appears to be more about the spatial pattern of this plaque progression, and not so much about the total amount found in brains. We saw a difference in the spatial distribution of plaques among cognitive declining and stable patients whose cognitive function had been measured over a 12-year period. They had similar amounts of amyloid plaque, just in different spots,’ Dr. Davatzikos said. ‘This is important because it potentially answers questions about the variability seen in clinical research among patients presenting plaque. It accumulates in different spatial patterns for different patients, and it’s that pattern growth that may determine whether your memory declines.’
The team, including first author Rachel A. Yotter, PhD, a postdoctoral researcher in the Section for Biomedical Image Analysis, retrospectively analysed the PET PiB scans of 64 patients from the NIA’s Baltimore Longitudinal Study of Aging whose average age was 76 years old. For the study, researchers created a unique picture of patients’ brains by combining and analysing PET images measuring the density and volume of amyloid plaque and their spatial distribution within the brain. The radiotracer PiB allowed investigators to see amyloid temporal changes in deposition.
Those images were then compared to California Verbal Learning Test (CLVT) scores, among other tests, from the participants to determine the longitudinal cognitive decline. The group was then broken up into two subgroups: the most stable and the most declining individuals (26 participants).

Despite lack of significant difference in the total amount of amyloid in the brain, the spatial patterns between the two groups (stable and declining) were different, with the former showing relatively early accumulation in the frontal lobes and the latter in the temporal lobes.

A particular area of the brain may be affected early or later depending on the amyloid trajectory, according to the authors, which in turn would affect cognitive impairment. Areas affected early with the plaque include the lateral temporal and parietal regions, with sparing of the occipital lobe and motor cortices until later in disease progression.

‘This finding has broad implications for our understanding of the relationship between cognitive decline and resistance and amyloid plaque location, as well as the use of amyloid imaging as a biomarker in research and the clinic,’ said Dr Davatzikos. ‘The next step is to investigate more individuals with mild cognitive impairment, and to further investigate the follow-up scans of these individuals via the BLSA study, which might shed further light on its relevance for early detection of Alzheimer’s.’ Perelman School of Medicine at the University of Pennsylvania

An international consortium has shown for the first time evidence of substantial overlap of genetic risk factors shared between bipolar disorder, major depressive disorder and schizophrenia and less overlap between those conditions and autism and attention deficit-hyperactivity disorder (ADHD), according to a study.
The root cause of psychiatric illnesses such as bipolar disorder, major depressive disorder schizophrenia, autism and ADHD is not fully understood. For more than 125 years, clinicians have based diagnosis on a collection of symptoms observed in patients.

But, scientists have since identified that the five psychiatric disorders share a common genetic link and are now moving toward understanding the molecular underpinnings of psychiatric illness. The precise degree to which these disorders share common ground has remained unknown, until now.

The project is led by the Cross-Disorder Group of the Psychiatric Genomics Consortium and is the largest genetic study of psychiatric illness to date.

The findings provide insight into the biological pathways that may predispose an individual to disease and could ultimately lead to the development of new therapeutic avenues to treat the five major psychiatric illnesses.

‘This is a very large scale study using a new, innovative statistical method,’ said study co-senior author Kenneth S. Kendler, M.D., professor of psychiatry, and human and molecular genetics in the Virginia Commonwealth University School of Medicine, and an internationally recognised psychiatric geneticist.

‘Prior to this model, we have not been able to address these questions. These results give us by far the clearest picture available to date of the degree of genetic similarity between these key psychiatric disorders. We hope that this will help us both in developing a more scientifically based diagnostic system and understanding the degree of sharing of the biological foundation these illnesses,’ he said.

The study builds on findings published earlier this year in The Lancet, which reported that specific single nucleotide polymorphisms, or SNPs, are associated with a range of psychiatric disorders that can occur during childhood or adulthood.

Next, the group will examine other disorders for which molecular genetic data is accumulating including eating disorders, obsessive compulsive disorder and drug use disorders.

Since 2007, the Cross-Disorder Group of the Psychiatric Genomics Consortium has reviewed scientific literature of genome-wide association studies, or GWAS, on psychiatric disorders. To date, GWAS data from more than 19 countries has been gathered by the consortium. Virginia Commonwealth University