Category Archives: Research News (General)

Patients who had a diagnosis of Parkinson’s disease (PD) with dementia (PDD) or dementia with Lewy bodies (DLB) and had higher levels of Alzheimer’s disease (AD) pathology in their donated post-mortem brains also had more severe symptoms of these Lewy body diseases (LBD) during their lives, compared to those whose brains had less AD pathology, according to new research. In particular, the degree of abnormal tau protein aggregations, indicative of AD, most strongly matched the clinical course of the LBD patients who showed evidence of dementia prior to their deaths, according to the study, which was published in The Lancet Neurology.

The team used post-mortem brain tissue donated by 213 patients with LBD and associated dementia, which was confirmed during autopsies to have alpha-synuclein pathology. They paired the tissue analysis with the patients’ detailed medical records. This unique study combined data from eight academic memory or movement disorder centers.

LBD is a family of related brain disorders made up of the clinical syndromes of PD, without or with dementia or DLB. LBD is associated with clumps of misshapened alpha-synuclein proteins. On the other hand, AD pathology is made up of clusters of the protein beta-amyloid called plaques and twisted strands of the protein tau, called tangles. Patients with LBD may have varying amounts of AD pathology, in addition to alpha-synuclein pathology.

Treatments directed at tau and amyloid-beta proteins are currently being tested in patients with Alzheimer’s disease. This study could help in selecting appropriate patients for trials of emerging therapies targeting these proteins singly or in combination with emerging therapies targeting alpha-synuclein protein in LBD.

The study suggests that Lewy body pathology may be the primary driver of disease seen in the patients; whereas, AD pathology has an impact on the overall course of disease.

None of the LBD patients had a clinical diagnosis of AD, but their post-mortem brain tissue revealed varying amounts of AD neuropathology. Post-mortem analysis of five brain regions per patient showed that they fell into one of four categories of AD pathology: 23 percent negligible or no AD, 26 percent had low-level, 21 percent intermediate, and 30 percent had high-level.

Increasing severity of AD pathology correlated with a shortened time from motor symptoms to the onset of dementia and death, with the most significant trends seen in the intermediate- and high-level AD groups compared to the low-level and no AD groups. Tau pathology, in particular, was the strongest predictor of a shorter time to dementia and death. AD pathology was also higher in patients who were older at the time of onset of motor symptoms and dementia.

The team also found that two relevant genetic variants in sequences of the patients’ DNA samples correlated with the amount of AD pathology. The frequency of a genetic variant in a gene coding for a protein involved in cholesterol metabolism (APOE, the most common risk factor for AD) was more frequent in patients who were in the intermediate or high AD pathology group compared to those in the low-level or no AD group. Interestingly, a variation in the gene for the protein GBA (a risk factor for LBD) was more frequent in patients without significant AD pathology. This gene is associated with LBD overall but not the subgroup with AD pathology.

In the brain, the enzyme GBA normally aids in the breakdown of worn out and misshapened proteins, such as alpha-synuclein. Together these findings suggest that genetic risk factors could influence the amount of AD pathology in LBD. Further understanding of the relationships between genetic risk factors and AD and alpha-synuclein pathology will help improve treatments for these disorders.

Paper: “Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis”
Reprinted from materials provided by the Perelman School of Medicine at the University of Pennsylvania.
 

Researchers have identified a naturally occurring molecule that has the potential for preserving sites of communication between nerves and muscles in amyotrophic lateral sclerosis (ALS) and over the course of aging — as well as a molecule that interferes with this helpful process.

The discovery in mice has implications for patients with ALS, also known as Lou Gehrig’s disease.

Published in The Journal of Neuroscience, the research team describes a growth factor called FGFBP1, which is secreted by muscle fibers and maintains neuromuscular junctions — a critical type of synapse that allows the spinal cord to communicate with muscles, sending signals from the central nervous system to create movements.

In mouse models of ALS, a growth factor associated with the immune system, called TGF-beta, emerges and prevents muscles from secreting factors needed to maintain their connections with neurons.

“TGF-beta is upregulated in ALS and in turn blocks expression of FGFBP1, which is released by muscle fibers to preserve the integrity of the neuromuscular junction,” said Gregorio Valdez, who led the study. “The body is trying to help itself by generating more TGF-beta. Unfortunately, TGF-beta accumulates at the synapse where it blocks expression of FGFBP1, accelerating degeneration of the neuromuscular junction.”

FGFBP1 also gradually decreases during aging, but more precipitously in ALS, because TGF-beta accumulates at the synapse, according to the researchers.

Paper: “Muscle fibers secrete FGFBP1 to slow degeneration of neuromuscular synapses during aging and progression of ALS”
Reprinted from materials provided by Virginia Tech.

Researchers have discovered that mice with Huntington’s disease (HD) suffer defects in muscle maturation that may explain some symptoms of the disorder. The study, which was published in The Journal of General Physiology, suggests that HD is a disease of muscle tissue as well as a neurodegenerative disorder and that therapies targeting skeletal muscle may improve patients’ motor function.

HD is a progressive, and ultimately fatal, disorder caused by a mutation in the huntingtin gene that results in the production of defective huntingtin RNA and protein molecules that disrupt various cellular processes. The cognitive and psychiatric disturbances associated with HD, including memory loss and mood swings, are thought to result from the death of neurons in the striatum and cerebral cortex. But some of the disease’s motor symptoms, such as involuntary movements and muscle rigidity, could arise from the effects of mutant huntingtin in skeletal muscle.

The researchers previously found that mice with an early-onset form of HD showed skeletal muscle defects at late stages of the disease, particularly a decrease in the function of a protein called ClC-1, which conducts chloride ions into the cell. This appeared to be caused by defective processing of the messenger RNA encoding ClC-1 and contributed to muscle hyperexcitability, potentially causing some of the motor symptoms associated with HD. But the loss of ClC-1 function could simply be a late response to the death of neurons innervating skeletal muscle; whether the chloride channel is affected during the onset and progression of HD remained unclear.

In the new study, the researchers examined their HD model mice throughout the course of the disease. They found that the RNA encoding ClC-1 was misprocessed in both HD and control mice when they were young, but, as they grew older, only healthy animals were able to start correctly processing the RNA to produce functional ClC-1. Thus, even before their motor symptoms began to appear, ClC-1 function was reduced in the skeletal muscle of HD mice compared with healthy control animals.

This suggested that muscle maturation might be disrupted in HD mice. The reseachers found that HD mice expressed a form of the muscle motor protein myosin that is usually only produced in newborn mouse muscle. Moreover, they identified similar defects in muscle maturation in a different strain of mice with adult-onset HD.

The researchers say that their results could provide a new opportunity to improve patient care by targeting skeletal muscle tissue. In addition, researchers and clinicians may be able to use the skeletal muscle defects as biomarkers to track the progress of HD, a much easier task than examining patients’ brain tissue.

New details learned about a key cellular protein could lead to treatments for neurodegenerative diseases such as Parkinson’s, Huntington’s, Alzheimer’s, and amyotrophic lateral sclerosis (ALS).

At their root, these disorders are triggered by misbehaving proteins in the brain. The proteins misfold and accumulate in neurons, inflicting damage and eventually killing the cells. In a new study, researchers used a different protein, Nrf2, to restore levels of the disease-causing proteins to a normal, healthy range, thereby preventing cell death.

The researchers tested Nrf2 in two models of Parkinson’s disease: cells with mutations in the proteins LRRK2 and alpha-synuclein. By activating Nrf2, the researchers turned on several “house-cleaning” mechanisms in the cell to remove excess LRRK2 and alpha-synuclein.

In the study, published in the Proceedings of the National Academy of Sciences, the scientists used both rat neurons and human neurons created from induced pluripotent stem cells. They then programmed the neurons to express Nrf2 and either mutant LRRK2 or alpha-synuclein. Using a one-of-a-kind robotic microscope, the researchers tagged and tracked individual neurons over time to monitor their protein levels and overall health. They took thousands of images of the cells over the course of a week, measuring the development and demise of each one.

The scientists discovered that Nrf2 worked in different ways to help remove either mutant LRRK2 or alpha-synuclein from the cells. For mutant LRRK2, Nrf2 drove the protein to gather into incidental clumps that can remain in the cell without damaging it. For alpha-synuclein, Nrf2 accelerated the breakdown and clearance of the protein, reducing its levels in the cell.

The scientists say that Nrf2 itself may be difficult to target with a drug because it is involved in so many cellular processes, so they are now focusing on some of its downstream effects. They hope to identify other players in the protein regulation pathway that interact with Nrf2 to improve cell health and that may be easier to drug.

Paper: “Nrf2 mitigates LRRK2- and α-synuclein–induced neurodegeneration by modulating proteostasis”
Reprinted from materials provided by Gladstone Institutes.

Parkinson’s disease (PD) and other “synucleinopathies” are known to be linked to the misfolding of alpha-synuclein protein in neurons. Less clear is how this misfolding relates to the growing number of genes implicated in PD through analysis of human genetics. In two studies published in Cell Systems, researchers explain how they used a suite of novel biological and computational methods to shed light on the question.

To start, they created two ways to systematically map the footprint of alpha-synuclein within living cells. “In the first paper, we used powerful and unbiased genetic tools in the simple Baker’s yeast cell to identify 332 genes that impact the toxicity of alpha-synuclein,” explained Vikram Khurana, first and co-corresponding author on the studies. “Among them were multiple genes known to predispose individuals to Parkinson’s–so we show that various genetic forms of Parkinson’s are directly related to alpha-synuclein. Moreover, the results showed that many effects of alpha-synuclein have been conserved across a billion years of evolution from yeast to human,” he said.

“In the second paper, we created a spatial map of alpha-synuclein, cataloging all the proteins in living neurons that were in close proximity to the protein,” explained Chee Yeun Chung, who co-led both studies with Khurana. The mapping was achieved without disturbing the native environment of the neuron, by tagging alpha-synuclein with an enzyme–APEX–that allowed proteins less than 10 nanometers away from synuclein to be marked with a trackable fingerprint.

Remarkably, the maps derived from these two processes were closely related and converged on the same Parkinson’s genes and cellular processes. Whether in a yeast cell or in a neuron, alpha synuclein directly interfered with the rate of production of proteins in the cell, and the transport of proteins between cellular compartments.

Finally, the authors addressed two major challenges for any study that generates large data-sets of individual genes and proteins in model organisms like yeast: How to assemble the data into coherent maps? And how to integrate information across species, in this case from yeast to human?

Enter computational biologist Jian Peng: “First, we had to figure out much better methods to find human counterparts of yeast genes, and then we had to arrange the humanized set of genes in a meaningful way,” he explained. “The result was a new suite of computational tools that uses machine learning algorithms to visualize patterns and interaction networks based on genes that are highly conserved from yeast to humans–and then makes predictions about the additional genes that are part of the alpha-synuclein toxicity response in humans.”

This analysis produced networks that mapped out how alpha-synuclein is related to other Parkinson’s genes through well-defined molecular pathways. “We now have a system to look at how seemingly unrelated genes come together to cause Parkinson’s and how they are related to the protein that misfolds in this disease,” said Khurana. To confirm their work, the researchers generated neurons from Parkinson’s patients with different genetic forms of the disease. They showed that the molecular maps generated from their analyses allowed them to identify abnormalities shared among these distinct forms of Parkinson’s. Prior to this, there was no obvious molecular connection between the genes implicated in these varieties of PD. “We believe these methods could pave the way for developing patient-specific treatments in the future,” Khurana observed.

Papers: “In situ proteomic approaches connect alpha synuclein directly to endocytic trafficking and mRNA metabolism in neurons” and “Genome-scale networks link neurodegenerative disease genes to alpha-synuclein through specific molecular pathways.“
Reprinted from materials provided by the Whitehead Institute.

Older people who followed a Mediterranean diet retained more brain volume over a three-year period than those who did not follow the diet as closely, a new study published in Neurology shows. But contrary to earlier studies, eating more fish and less meat was not related to changes in the brain.

The Mediterranean diet includes large amounts of fruits, vegetables, olive oil, beans and cereal grains such as wheat and rice, moderate amounts of fish, dairy and wine, and limited red meat and poultry.

Researchers gathered information on the eating habits of 967 Scottish people around age 70 who did not have dementia. Of those people, 562 had an MRI brain scan around age 73 to measure overall brain volume, gray matter volume and thickness of the cortex, which is the outer layer of the brain. From that group, 401 people then returned for a second MRI at age 76. These measurements were compared to how closely participants followed the Mediterranean diet.

The participants varied in how closely their dietary habits followed the Mediterranean diet principles. People who didn’t follow as closely to the Mediterranean diet were more likely to have a higher loss of total brain volume over the three years than people who followed the diet more closely. The difference in diet explained 0.5 percent of the variation in total brain volume, an effect that was half the size of that due to normal aging.

The results were the same when researchers adjusted for other factors that could affect brain volume, such as age, education and having diabetes or high blood pressure.

There was no relationship between grey matter volume or cortical thickness and the Mediterranean diet.

Paper: “Mediterranean-type diet and brain structural change from 73 to 76 years in a Scottish cohort”
Reprinted from materials provided by the American Academy of Neurology.

Researchers have identified a link between Huntington’s disease and dysfunction of the subthalamic nucleus, a component of the basal ganglia, a group of brain structures critical for movement and impulse control.

Huntington’s disease is characterized by the progressive loss of nerve cells in the brain and affects approximately 1 in 10,000 people. This fatal disorder is caused by a hereditary defect in a single gene.

The study was published in the journal eLife.

Using mice genetically engineered to carry the Huntington’s disease gene, scientists discovered the electrical activity of the subthalamic nucleus was lost. Furthermore, impaired subthalamic activity was caused by anomalous receptor signaling, leading to defective energy metabolism and accumulation of damaging oxidants. The authors also found abnormalities in the subthalamic nucleus occur earlier than in other brain regions, and that subthalamic nucleus nerve cells progressively degenerate as the mice age, mirroring the human pathology of Huntington’s disease.

Currently, there is no cure for Huntington’s disease; treatment can only alleviate some of the symptoms. A better understanding of aberrant brain receptor signaling that leads to nerve cell dysfunction could reveal a target for therapy, according to the authors.

Paper: “Early dysfunction and progressive degeneration of the subthalamic nucleus in mouse models of Huntington’s disease”
Reprinted from materials provided by Northwestern Medicine.

The main changes in our brains as we get older are in the brain cells with a supporting role, called glial cells, scientists have found.

The surprising finding is published in the journal Cell Reports.

The researchers also found that the greatest changes in glial cells as we age are in the brain regions most often damaged by neurodegenerative disease, like Alzheimer’s and Parkinson’s.

The discovery suggests the interactions between glial cells and neuronal cells, the nerve cells active in mental function and forming memories, should be a focus of future dementia, Alzheimer’s and Parkinson’s disease research.

The scientists analysed brain tissue samples from 480 healthy people who were between 16 and 106 years old when they died. They looked at patterns of gene expression in neuron and glial cells in 10 different brain regions.

They used dedicated computational analyses – involving data mining and machine learning approaches – to examine the cell populations present in images scanned from stained brain sections. Each image would typically include hundreds of thousands of brain cells and is scanned in high resolution.

Most of the samples were provided by a UK brain bank, the Sudden Death MRC brain bank, based in Edinburgh, which stores post mortem brain tissue donated for research. This large resource, confirmed by samples from other brain banks, allowed the team to tell the story of how healthy human brains age.

The team’s findings and the new resource of data this research has generated provide an important foundation for future studies that apply a similar approach to learn more about neurodegenerative diseases.

Paper: “Major Shifts in Glial Regional Identity Are a Transcriptional Hallmark of Human Brain Aging”

Reprinted from materials provided by the Francis Crick Institute.

A new laboratory study provides clues on a particular pathway of alpha-synuclein diffusion.

Researchers have found that alpha-synuclein, a protein involved in a series of neurological disorders including Parkinson’s disease, is capable of travelling from brain to stomach and that it does so following a specific pathway. The study, carried out in rats, sheds new light on pathological processes that could underlie disease progression in humans. It was published in the journal Acta Neuropathologica.

Alpha-synuclein occurs naturally in the nervous system, where it plays an important role in synaptic function. However, in Parkinson’s disease, dementia with Lewy bodies and other neurodegenerative diseases termed “synucleinopathies”, this protein is accumulated within neurons, forming pathological aggregates. Distinct areas of the brain become progressively affected by this condition. The specific mechanisms and pathways involved in this widespread distribution of alpha-synuclein pathology remain to be fully elucidated. Clinical and experimental evidence suggests however that alpha-synuclein – or abnormal forms of it – could “jump” from one neuron to another and thus spread between anatomically interconnected regions.

Alpha-synuclein lesions have also been observed within neurons of the peripheral nervous system, such as those in the gastric wall. In some Parkinson’s patients, these lesions were detected at early disease stages.

With the help of a tailor-made viral vector the researchers triggered production of human alpha-synuclein in rats. The virus transferred the blueprint of the human alpha-synuclein gene specifically into neurons of the midbrain, which then began producing large quantities of the foreign protein, which is associated with some forms of Parkinson’s disease.

Tissue analysis by collaborators revealed that, after its midbrain expression, the protein was capable of reaching nerve endings in the gastric wall. Further work established the precise pathway used by human alpha-synuclein to complete its journey from the brain to the stomach. The protein first moved from the midbrain to the “medulla oblongata”, the lowest brainstem region; in the medulla oblongata, it was detected within neurons whose long fibers form the “vagus nerve”. Fibers of the vagus nerve connect the brain to a variety of internal organs; travelling within these fibers, human alpha-synuclein was ultimately able to reach the gastric wall about six months after its initial midbrain expression. Progressive accumulation of human alpha-synuclein within gastric nerve terminals was accompanied by evidence of neuronal damage.

Paper: “Brain-to-stomach transfer of α-synuclein via vagal preganglionic projections”
Reprinted from materials provided by DZNE.

In a recent study of adults with early memory loss, a research team found that practice of a simple meditation or music listening program may have multiple benefits for older adults with preclinical memory loss.

In this randomized controlled trial, 60 older adults with subjective cognitive decline (SCD), a condition that may represent a preclinical stage of Alzheimer’s disease, were assigned to either a beginner meditation (Kirtan Kriya) or music listening program and asked to practice 12 minutes/day for 12 weeks. As detailed in a paper published by the Journal of Alzheimer’s Disease, both the meditation and music groups showed marked and significant improvements in subjective memory function and objective cognitive performance at three months. These included domains of cognitive functioning most likely to be affected in preclinical and early stages of dementia (e.g., attention, executive function, processing speed, and subjective memory function). The substantial gains observed in memory and cognition were maintained or further increased at 6 months (3 months post-intervention).

Both intervention groups also showed improvements in sleep, mood, stress, well-being and quality of life, with gains that were that were particularly pronounced in the meditation group; again, all benefits were sustained or further enhanced at 3 months post-intervention.

The findings of this trial suggest that two simple mind-body practices, Kirtan Kriya meditation and music listening, may not only improve mood, sleep, and quality of life, but also boost cognition and help reverse perceived memory loss in older adults with SCD.

Paper: “Meditation and Music Improve Memory and Cognitive Function in Adults with Subjective Cognitive Decline: A Pilot Randomized Controlled Trial”
Reprinted from materials provided by IOS Press.