Author Archives: jpnd

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.