Yearly Archives: 2017

Researchers have found the first direct evidence that autoimmunity—in which the immune system attacks the body’s own tissues—plays a role in Parkinson’s disease, the neurodegenerative movement disorder. The findings raise the possibility that the death of neurons in Parkinson’s could be prevented by therapies that dampen the immune response.

The study was published in Nature.

Scientists once thought that neurons were protected from autoimmune attacks. However, in a 2014 study, the researchers demonstrated that dopamine neurons (those affected by Parkinson’s disease) are vulnerable because they have proteins on the cell surface that help the immune system recognize foreign substances. As a result, they concluded, T cells had the potential to mistake neurons damaged by Parkinson’s disease for foreign invaders.

The new study found that T cells can be tricked into thinking dopamine neurons are foreign by the buildup of damaged alpha-synuclein proteins, a key feature of Parkinson’s disease.

In the study, the researchers exposed blood samples from 67 Parkinson’s disease patients and 36 age-matched healthy controls to fragments of alpha-synuclein and other proteins found in neurons. They analyzed the samples to determine which, if any, of the protein fragments triggered an immune response. Little immune cell activity was seen in blood samples from the controls. In contrast, T cells in patients‘ blood samples, which had been apparently primed to recognize alpha-synuclein from past exposure, showed a strong response to the protein fragments. In particular, the immune response was associated with a common form of a gene found in the immune system, which may explain why many people with Parkinson’s disease carry this gene variant.

The researchers hypothesize that autoimmunity in Parkinson’s disease arises when neurons are no longer able to get rid of abnormal alpha-synuclein. The team is now analyzing these responses in additional patients, and are working to identify the molecular steps that lead to the autoimmune response in animal and cellular models.

Paper: “T cells of Parkinson’s disease patients recognize alpha-synuclein peptides”
Reprinted from materials provided by Columbia University Medical Center.

Scientists have, for the first time, characterized the molecular markers that make the brain’s front lines of immune defense—cells called microglia—unique. In the process, they discovered further evidence that microglia may play roles in a variety of neurodegenerative and psychiatric illnesses, including Alzheimer’s, Parkinson’s and Huntington’s diseases as well as schizophrenia, autism and depression.

Genes that have previously been linked to neurological diseases are turned on at higher levels in microglia compared to other brain cells, the team reported in a study published in Science.

While the link between microglia and a number of disorders has been explored in the past, the new study offers a molecular basis for this connection.

Microglia are notoriously hard to study. They can’t be easily grown in a culture dish and quickly die outside of a living brain. Setting out to characterize the molecular characteristics of microglia, the researchers collected brain tissue from 19 patients, all of who were having brain surgery for epilepsy, a brain tumor or a stroke. They isolated microglia from areas of tissue that were unaffected by disease, as well as from mouse brains, and then set out to study the cells.

The team used a variety of molecular and biochemical tests to characterize which genes are turned on and off in microglia, how the DNA is marked up by regulatory molecules, and how these patterns change when the cells are cultured. Microglia, they found, have hundreds of genes that are more highly expressed than other types of macrophages, as well as distinct patterns of gene expression compared to other types of brain cells.

Next, the researchers analyzed whether any of the genes that were upregulated in microglia compared to other cells had been previously implicated in disease. Genes linked to a variety of neurodegenerative and psychiatric diseases, they found, were highly expressed in microglia.

For Alzheimer’s, more than half of the genes known to affect a person’s risk of developing the disease were expressed more highly in microglia than other brain cells.

Paper: “An environment-dependent transcriptional network specifies human microglia identity”
Reprinted from materials provided by the Salk Institute.

Researchers have identified two groups of neurons that can be turned on and off to alleviate the movement-related symptoms of Parkinson’s disease. The activation of these cells in the basal ganglia relieves symptoms much longer than current therapies, like deep brain stimulation and pharmaceuticals.

The study was published in the journal Nature Neuroscience.

The study used optogenetics in a mouse model of Parkinson’s to better understand the neural circuitry involved in Parkinson’s disease, and could provide the basis for new experimental treatment protocols.

Parkinson’s disease is caused when the dopamine neurons that feed into the brain’s basal ganglia die and cause the basal ganglia to stop working, preventing the body from initiating voluntary movement.

The basal ganglia is the main clinical target for treating Parkinson’s disease, but currently used therapies do not offer long-term solutions.

To better understand how the neurons in the basal ganglia behave in Parkinson’s, the researchers looked at the inner circuitry of the basal ganglia. They chose to study one of the structures that makes up that region of the brain, a nucleus called the external globus pallidus (GPe). The GPe is known to contribute to suppressing motor pathways in the basal ganglia, but little is known about the individual types of neurons present in the GPe, their role in Parkinson’s disease or their therapeutic potential.

The research group used optogenetics, a technique that turns genetically tagged cells on and off with light. They targeted two cell types in a mouse model for Parkinson’s disease: PV-GPe neurons and Lhx6-GPe neurons. They found that by elevating the activity of PV-GPe neurons over the activity of the Lhx6-GPe neurons, they were able to stop aberrant neuronal behavior in the basal ganglia and restore movement in the mouse model for at least four hours — significantly longer than current treatments.

While optogenetics is used only in animal models, the researchers say their findings could lead to a new, more effective deep brain stimulation protocol.

Paper: “Cell-specific pallidal intervention induces long-lasting motor recovery in dopamine-depleted mice”
Reprinted from materials provided by Carnegie Mellon University.

A new large-scale genetic study found that low body mass index (BMI) is likely not a causal risk factor for Alzheimer’s disease, as earlier research had suggested, according to a study published in the Journal of Clinical Endocrinology & Metabolism.

To examine the association between Alzheimer’s disease and low BMI, the researchers analyzed blood and DNA samples from 95,578 participants in the Copenhagen General Population Study (CGPS). Of the participants, 645 individuals developed Alzheimer’s disease.

The researchers analyzed the study participants‘ DNA for the presence of five genetic variants that have strong associations with BMI. Based on how many variants were found, participants were divided into four groups to reflect the likelihood of low BMI. The researchers also analyzed data from up to 249,796 individuals participating in the Genetic Investigation of ANthropometric Traits (GIANT) consortium for the genetic variants closely linked to low BMI.

The analysis found the presence of the genetic variants tied to low BMI was not associated with increased risk of Alzheimer’s disease. For comparison, the researchers examined if individuals with genetic variants connected to high BMI were more likely to have type 2 diabetes and did find the expected causal relationship.

Paper: “Body Mass Index and Risk of Alzheimer Disease: a Mendelian Randomization Study of 399,536 Individuals”
Reprinted from materials provided by The Endocrine Society.

A new study published in the journal Scientific Reports shows that bone marrow stem cell transplants helped improve motor functions and nervous system conditions in mice with amyotrophic lateral sclerosis (ALS) by repairing damage to the blood-spinal cord barrier.

The researchers say the results of their experiment are an early step in pursuing stem cells for potential repair of the blood-spinal cord barrier, which has been identified as key in the development of ALS.

Using stem cells harvested from human bone marrow, researchers transplanted cells into mice modeling ALS and already showing disease symptoms. The transplanted stem cells differentiated and attached to vascular walls of many capillaries, beginning the process of blood-spinal cord barrier repair.

The stem cell treatment delayed the progression of the disease and led to improved motor function in the mice, as well as increased motor neuron cell survival, the study reported. Because stem cells have the ability to develop into many different cell types in the body, researchers have focused on using stem cells to restore function lost through neurodegenerative disorders or injuries.

Damage to the barrier between the blood circulatory system and the central nervous system has been recently recognized as a factor in ALS development, leading researchers to work on targeting the barrier for repair as a potential strategy for ALS therapy.

In this study, the ALS mice were given intravenous treatments of one of three different doses of the bone marrow stem cells. Four weeks after treatment, the scientists determined improved motor function and enhanced motor neuron survival. The mice receiving the higher doses of stem cells fared better in the study.

The transplanted stem cells had differentiated into endothelial cells – which form the inner lining of a blood vessel, providing a barrier between blood and spinal cord tissue — and attached to capillaries in the spinal cord. Furthermore, the researchers observed reductions in activated glial cells, which contribute to inflammatory processes in ALS.

Paper: “Endothelial and Astrocytic Support by Human Bone Marrow Stem Cell Grafts into Symptomatic ALS Mice towards Blood-Spinal Cord Barrier Repair”
Reprinted from materials provided by USF Health.

Scientists have discovered a potential brain imaging predictor for dementia, which illustrates that changes to the brain’s structure may occur years prior to a diagnosis, even before individuals notice their own memory problems.

The study, published in the Neurobiology of Aging, looked at older adults who are living without assistance and who were unaware of any major memory problems, but scored below the normal benchmark on a dementia screening test.

Within these older adults, researchers also found evidence of less brain tissue in the same subregion of the brain where Alzheimer’s disease originates (the anterolateral entorhinal cortex located in the brain’s temporal lobe).

This is the first to measure this particular brain subregion in older adults who do not have a dementia diagnosis or memory problems that affect their day-to-day routine. It is also the first study to demonstrate that performance on the Montreal Cognitive Assessment (MoCA) dementia screening test is linked to the volume (size) of this subregion, along with other brain regions affected early in the course of Alzheimer’s disease.

The team studied 40 adults between the ages of 59 and 81 who live independently (or with a spouse) at home. All participants were tested on the MoCA. Those scoring below 26 — a score that indicates a potential problem in memory and thinking skills and suggests further dementia screening is needed — were compared to those scoring 26 and above.

Scientists were able to reliably measure the volume of the anterolateral entorhinal cortex by using high-resolution brain scans that were collected for each participant.

The strongest volume differences were found in the exact regions of the brain in which Alzheimer’s disease originates. The researchers are planning a follow-up study to determine whether the individuals who demonstrated poor thinking and memory abilities and smaller brain volumes indeed go on to develop dementia.

Paper: “Anterolateral entorhinal cortex volume predicted by altered intra-item configural processing”
Reprinted from materials provided by Baycrest Centre for Geriatric Care.