Category Archives: Research News (General)

A multi-institutional team of researchers has discovered how a potential treatment strategy for Huntington’s disease (HD) produces its effects, verified its action in human cells and identified a previously unknown deficit in neural stem cells from patients with HD.

In their report, published in Proceedings of the National Academy of Sciences, the team describes finding how a group of compounds activates the NRF2 molecular pathway, which protects cells from several damaging influences, and also discovering that NRF2-mediated activity appears to be impaired in neural stem cells from the brains of HD patients.

A 2016 study by the same researchers identified a compound, which the investigators named MIND4, that appeared to protect against HD-associated neurodegeneration in two ways — by activating the NRF2-mediated pathway and by inhibiting the regulatory enzyme SIRT2, a strategy also being investigated to treat Parkinson’s disease. A related compound, called MIND4-17, was found to only activate the NRF2 pathway but to do so more powerfully than did MIND4. The current investigation’s overall goal was to examine whether the NRF2 activation responses observed in that study were also present in human cells, indicating their potential for therapeutic development.

The investigators found that MIND4-17 acts by mimicking the same process that activates the NRF2 pathway in response to oxidative stress. In stress-free conditions NRF2 is bound into a complex by two other proteins, one of which mediates a process leading to the breakdown of NRF2. MIND4-17 binds to and modifies the mediating protein in way that changes the shape and arrests formation of the protein complex, thereby allowing newly synthesized NRF2 to escape degradation and move to the nucleus where it can activate protective antioxidant genes.

NRF2 activation also induced anti-inflammatory effects in microglia and macrophages, immune cells known to infiltrate the brain in late-stage HD; and treatment with MIND4, which crosses the blood-brain barrier, reduced levels of a key inflammatory protein in a mouse model of HD.

In human neural stem cells from patients with HD — cells reflecting a range of the CAG nucleotide repeats found in the mutated gene that underlies the disorder — NRF2 activation in response to MIND4-17 was found to be reduced at levels correlating with the number of repeats.

Since MIND4-17 is unable to penetrate the blood brain barrier, future work is needed to develop powerful NRF2-activating compounds with enhanced brain permeability and to test their efficacy in models of HD and other neurodegenerative disorders.

Paper: “KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington’s disease patients”

Reprinted from materials provided by Massachusetts General Hospital

For people with dementia, communicating needs, emotions and interacting with others becomes increasingly difficult as communication deteriorates as dementia progresses. Problems in communicating lead to misinterpretations and misunderstandings, which often cause considerable stress for family members, especially the spouse caregivers, as well as the patients.

But all is not lost according to the first study to look at and measure communication outcomes in both the caregiver spouse and the patient with dementia. In fact, researchers have found that “practice makes perfect” with the right intervention and a tool that can accurately measure couples’ communication. Results from the study are published in the journal Issues in Mental Health Nursing.

For the study, the researchers videotaped and later analyzed and measured 118 conversations between 15 patients with varying degrees of dementia and their spouses — married an average of 45 years — to evaluate the effects of a 10-week communication-enhancement intervention on participants’ communication and mental health.

Caregivers were taught to communicate in a manner that was clear, succinct and respectful, and to avoid testing memory and arguing. Spouses with dementia were given the opportunity to practice their conversation skills with a member of the research team who was trained in communication deficits associated with dementia as well as the intervention. Conversations were recorded at the couples’ homes. After setting up the video camera, the researchers conducted the intervention and then left the room for 10 minutes. Couples were instructed to converse on a topic of their choice for 10 minutes.

Unlike other measures of patient communication, the Verbal and Nonverbal Interaction Scale-CR (VNIS-CR) tool takes into account nonverbal behaviors, which account for more than 70 percent of communication, as well as verbal behaviors. VNIS-CR delineates social and unsociable behaviors, characterizes patient behaviors (not through the lens of a caregiver), and is targeted to spousal relationships in the home. Consisting of 13 social and 13 unsociable communication behaviors with both verbal and nonverbal items, the tool helps to describe sociable and unsociable communication in patients with dementia as they engage in conversations with their spouses.

The VNIS-CR could be used in clinical practice to describe changes in social communication abilities over time, as well as to educate spousal caregivers about the importance of encouraging sociable communication. Knowledge gained from using this tool could better guide the development of interventions to support intimate relationships and ultimately measure changes following those interventions.

Paper: “Preliminary Psychometric Properties of the Verbal and Nonverbal Interaction Scale: An Observational Measure for Communication in Persons with Dementia”
Reprinted from materials provided by Florida Atlantic University.

An international research team has identified a new type of neuron which might play a vital role in humans’ ability to navigate their environments. The discovery is an important step towards understanding how the brain codes navigation behaviour at larger scales and could potentially open up new treatment strategies for people with impaired topographical orientation such as Alzheimer’s patients.

The study was published in Nature Communications.

The ability to make fine-grained assessments of location is seated in the hippocampus, located in the temporal lobe. Research shows that the precise mechanism for navigation includes hippocampal place cells, which increase or decrease in electrical activity depending on one’s location.

Building on current research, the researchers investigated how large scale navigational knowledge is coded within the brain and whether this process indeed occurs in different structures within the temporal lobe.

They did this by training rats to perform a visually guided task in a figure-8 maze consisting of two loops that overlap in the middle lane. During the experiment, the researchers measured electrical activity in the brain by using a novel instrument which allowed the researchers to simultaneously record groups of neurons from four different areas. They recorded from the perirhinal cortex, hippocampus and two sensory areas. Recordings from the perirhinal cortex revealed sustained activity patterns. The level of electrical activity clearly rose and fell depending on the segment the rats were in and persisted throughout that entire segment.

The results were surprising, the researchers said, because the perirhinal cortex is currently thought to be associated with object recognition. They hypothesize that this represents a new type of neuron that helps the brain distinguish between different areas or ‘neighborhoods’ in the external environment.

The team’s results offer a first glimpse into how the brain is able to code navigation behaviour at larger scales and could be especially relevant for people with an impaired capacity for topographical orientation.

In addition to offering new insights into brain mechanisms for spatial navigation at different scales, the results may guide patients with Alzheimer’s or other diseases in using other spatial strategies than the ones most severely affected, the researchers say. The findings point to the perirhinal cortex as a target for treatment. Finally, research on neural replacement devices and assistive robots may benefit from this study.

Paper: “Perirhinal firing patterns are sustained across large spatial segments of the task environment”
Reprinted from materials provided by Universiteit van Amsterdam.

Although Parkinson’s disease is often associated with motor symptoms such as stiffness, poor balance and trembling, the first symptoms are often sensory and include a reduced sense of touch and smell. In a study on mice, researchers have now been able to identify neural circuits and mechanisms behind this loss of sensory perception. The study, which was published in Neuron, may open avenues to methods of earlier diagnosis.

In this study, researchers used a light puff of air to stimulate either the right or left whiskers of mice, some of which had an especially low number of dopamine cells, while using a new optogenetic tool called an optopatcher. Applying this technique, which enables the activity of neurons to be recorded during manipulation with light, they were able to see which neurons in the basal ganglia were active and when they transmitted signals.

The researchers report that the neurons in mice with very low levels of dopamine did not properly signal in response to whisker stimulation and could not accurately tell the difference between right and left. However, after being treated with a common Parkinson’s drug called L-DOPA, this ability was regained.

The researchers say they hope that the discovery will open the way for methods of earlier diagnosis.

Paper: “Dopamine Depletion Impairs Bilateral Sensory Processing in the Striatum in a Pathway-Dependent Manner”

Reprinted from materials provided by the Karolinska Institutet.

Tau proteins are involved in more than twenty neurodegenerative diseases, including various forms of dementia. These proteins clump together in patients’ brains to form neuronal tangles: protein aggregation that eventually coincides with the death of brain cells. Researchers have now discovered how tau disrupts the functioning of nerve cells, even before it starts forming tangles.

The study was published in Nature Communications.

In healthy circumstances, tau proteins are connected to the cytoskeleton of nerve cells, where they support the cells’ structural stability. In the nerve cells of patients, however, tau is dislodged from the cytoskeleton and ultimately tangles together to form protein accumulations that disrupt the nerve cell’s functioning.

But even before these protein accumulations are formed, the dislodged tau impedes the communication between nerve cells. The researchers say that they found that across fruit flies, rats, and human patients, dislodged tau ends up at nerve cell synapses, where it hooks into vesicles and inhibits communication between different nerve cells.

The next step, the researchers say, is to see if, in animal models, they can find ways to keep tau from hooking onto vesicles and, by extension, prevent nerve cell death.

Paper: “Tau association with synaptic vesicles causes presynaptic dysfunction”
Reprinted from materials provided by: VIB – Flanders Interuniversity Institute for Biotechnology

By studying cells from patients with motor neuron disease, also known as amyotrophic lateral sclerosis (ALS), researchers have revealed a detailed picture of how motor neurons — nerve cells in the brain and spinal cord that control our muscles and allow us to move, talk and breathe — decline and die.

The research, published in Cell Reports, also shows that healthy neuron-supporting cells called astrocytes may play a role in the survival of motor neurons in this type of ALS, highlighting their potential role in combating neurodegenerative diseases.

The team took skin cells from healthy volunteers and patients with a genetic mutation that causes ALS, and turned them into stem cells capable of becoming many other cell types. Using specific chemical signals, they then ‘guided’ the stem cells into becoming motor neurons and astrocytes.

Using a range of cellular and molecular techniques, the team tracked motor neurons over time to see what went wrong in the patient-derived cells compared to those from healthy people. They found that an important protein known as TDP-43 leaks out of the nucleus where it belongs, causing a chain reaction that damaged several crucial parts of the cell’s ‘machinery’. Defining the sequence of molecular events that led to motor neuron death in an experiment using human-derived cells is an important step forward.

The team suspected that astrocytes from the patients’ cells might also be affected, becoming less efficient over time and eventually dying. To test this, they mixed different combinations of healthy and ALS patient-derived motor neurons and astrocytes, and followed their fate using highly sensitive imaging approaches. They found that healthy astrocytes kept sick motor neurons alive and functioning for longer, but sick astrocytes struggled to keep even healthy motor neurons alive.

Paper: “Progressive motor neuron pathology and the role of astrocytes in a human stem cell model of VCP-related ALS”
Reprinted from materials provided by the Francis Crick Institute.

By using induced pluripotent stem cells to create endothelial cells that line blood vessels in the brain for the first time for a neurodegenerative disease, researchers have learned why Huntington’s disease patients have defects in the blood-brain barrier that contribute to the symptoms of this fatal disorder. The study, which is the first induced pluripotent stem cell-based model of the blood-brain barrier for a neurodegenerative disease, was published in Cell Reports.

The blood-brain barrier protects the brain from harmful molecules and proteins. It has been established that in Huntington’s and other neurodegenerative diseases there are defects in this barrier adding to HD symptoms. What was not known was whether these defects come from the cells that constitute the barrier or are secondary effects from other brain cells.

To answer that question, researchers reprogrammed cells from HD patients into induced pluripotent stem cells, then differentiated them into brain microvascular endothelial cells — those that form the internal lining of blood vessels and prevent leakage of blood proteins and immune cells.

The researchers discovered that blood vessels in the brains of HD patients become abnormal due to the presence of the mutated Huntingtin protein, the hallmark molecule linked to the disease. As a result, these blood vessels have a diminished capacity to form new blood vessels and are leaky compared to those derived from control patients.

The chronic production of the mutant Huntingtin protein in the blood vessel cells causes other genes within the cells to be abnormally expressed, which in turn disrupts their normal functions, such as creating new vessels, maintaining an appropriate barrier to outside molecules, and eliminating harmful substances that may enter the brain.

In addition, by conducting in-depth analyses of the altered gene expression patterns in these cells, the researchers identified a key signaling pathway known as the Wnt that helps explain why these defects occur. In the healthy brain, this pathway plays an important role in forming and preserving the blood-brain barrier. The researchers showed that most of the defects in HD patients’ blood vessels can be prevented when the vessels are exposed to a compound (XAV939) that inhibits the activity of the Wnt pathway.

Paper: “Huntington’s Disease iPSC-Derived Brain Microvascular Endothelial Cells Reveal WNT-Mediated Angiogenic and Blood-Brain Barrier Deficits”
Reprinted from materials provided by the University of California, Irvine.

Many diseases, including Parkinson’s disease, can be treated with electrical stimulation from an electrode implanted in the brain. However, the electrodes can produce scarring, which diminishes their effectiveness and can necessitate additional surgeries to replace them.

The question now is whether fibers that are only 30 microns in diameter can be adapted for electrical stimulation, drug delivery, and recording electrical activity in the brain. Such devices could be potentially useful for treating Parkinson’s disease or other neurological disorders, the researchers say.

Paper: “Making brain implants smaller could prolong their lifespan: Thin fibers could be used to deliver drugs or electrical stimulation, with less damage to the brain.”
Reprinted from materials provided by the Massachusetts Institute of Technology.

In a new study published in Molecular Psychiatry, researchers have measured how deposits of the pathological protein tau spread through the brain over the course of Alzheimer’s disease. Their results show that the size of the deposit and the speed of its spread differ from one individual to the next, and that large amounts of tau in the brain can be linked to episodic memory impairment.

Even in a very early phase of Alzheimer’s disease there is an accumulation of tau in the brain cells, where its adverse effect on cell function causes memory impairment. It is therefore an attractive target for vaccine researchers. For the present study, the research team used PET brain imaging to measure the spread of tau deposits as well as the amyloid plaque associated with Alzheimer’s disease, and charted the energy metabolism of the brain cells. They then examined how these three parameters changed over the course of the disease.

The study included 16 patients at different stages of Alzheimer’s disease. The patients were given a series of neurological memory tests and underwent PET scans at 17-month intervals. While all 16 participants had abundant amyloid plaque deposition in the brain, the size and speed of spread of their tau deposits differed significantly between individuals. A notable correlation between the size of the deposit and episodic memory impairment was also found, the researchers said, noting that this could explain differences in disease progression across patients.

Paper: “Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer’s disease dementia”
Reprinted from materials provided by Karolinska Institutet.

A new article published in JAMA Neurology compares survival rates among patients with synucleinopathies, including Parkinson’s disease, dementia with Lewy bodies, Parkinson’s disease dementia and multiple system atrophy with parkinsonism, with individuals in the general population.

The population-based study included all the residents of Minnesota’s Olmsted County and identified 461 patients with synucleinopathies and 452 patients without for comparison.

From 1991 through 2010, the 461 patients with a synucleinopathy diagnosis included 309 with Parkinson’s disease, 81 with dementia with Lewy bodies, 55 with Parkinson’s disease dementia and 16 with multiple system atrophy with parkinsonism. Parkinsonism was defined as the presence of at least 2 of 4 cardinal signs: rest tremor, bradykinesia, rigidity and impaired postural reflexes.

Of the 461 patients with synucleinopathies, 316 (68.6 percent) died during follow-up, while among the 452 participants used for comparison, 220 (48.7 percent) died during follow-up.

Overall, patients with synucleinopathies died about two years earlier than participants without in the comparison group. The highest risk of death was seen among patients with multiple system atrophy with parkinsonism, followed by patients with dementia with Lewy bodies, Parkinson’s disease dementia and Parkinson’s disease, according to the results.

Paper: “Survival and Causes of Death Among People With Clinically Diagnosed Synucleinopathies With Parkinsonism”
Reprinted from materials provided by The JAMA Network.