Researchers Funded by National MS Society Pinpoint Direct Damage to Nerve Connections in Mice, Independent of Myelin Damage

Summary

• Researchers have found evidence that microscopic connectors in the brain called “synapses” are directly damaged during the course of MS-like disease in mice, in an area of the brain linked to cognitive function.
• The damage appeared to be unrelated to myelin damage, and was linked  to a specific molecule called platelet-activating factor receptor.
• Further research will determine whether treatment that protects synapses in the hippocampus may preserve cognitive function in people with MS. The team is pursuing therapeutic candidates based on these findings.
• This research was funded in part by a National MS Society-American Brain Foundation (American Academy of Neurology) Clinician Scientist Development Award to Dr. Matthew Bellizzi.
• The team (Drs. Bellizzi, Harris Gelbard, and colleagues, from the University of Rochester Medical Center, in New York) has published results in The Journal of Neuroscience. (2016 Jan 27;36(4):1336-46.) 

Background:  MS involves immune attacks in the brain and spinal cord. During the course of MS, damage  occurs to the myelin that surrounds and protects nerve fibers, and nerve cells and their axons are also damaged.  Damage to nerve cells in MS has been linked to cognitive impairment, progressive disability and other symptoms.

The causes of nerve damage are not yet well understood, which has limited progress in developing therapies that prevent damage and preserve nerve function (neuroprotection) to slow or stop progressive disability. Some research has shown that microscopic connectors in the brain called “synapses” may be lost in some parts of the brain during the course of MS, but details have been lacking. Synapses are the point of communication between individual nerve cells, and they are critically important for all functions of the nervous system including memory. A  team at the University of Rochester has been attempting to determine the extent of damage to nerve cell fibers and synapses in brain, to find ways to protect nerves from damage.

The Study:  The team, led by Matthew Bellizzi, MD, PhD, and Harris Gelbard, MD, PhD (University of Rochester), studied mice with the MS-like disease EAE. They measured the density of synapses in an area of the brain called the hippocampus. The hippocampus is involved in memory function. Although myelin was preserved, synaptic density was reduced by 28%, compared with mice that did not have EAE.

In another study, the team grew nerve cells from the hippocampus in laboratory dishes, and then added brain cells called microglia. This made the synapses more vulnerable to damage, and this damage seemed to be dependent on signals from a molecule called platelet-activating factor receptor (PAFR). To test this, the team administered an experimental molecule – BN52021 – that inhibits PAFR. Administering this molecule before EAE developed did not prevent the disease, but preserved synapses.

This research was funded in part by a National MS Society-American Brain Foundation (American Academy of Neurology) Clinician Scientist Development Award to Dr. Matthew Bellizzi. The team published results in The Journal of Neuroscience. (2016 Jan 27;36(4):1336-46.)

Next Steps:  Further research will determine whether treatment that preserves synapses in the hippocampus can improve cognitive function in people with MS. According to a press release from the University of Rochester, the researchers are now focused on exploring potential therapeutic candidates based on these findings.

Read more about research to repair damaged tissue in MS
Read more about efforts to understand how MS affects cognitive function
Watch the educational video, Mood & Cognition in MS: [What you can do].

Study reveals brain network responsible for cognitive changes in multiple sclerosis

An estimated 2.3 million individuals are living with multiple sclerosis (MS) worldwide. Approximately half of all individuals with MS experience changes in cognition such as impaired concentration, attention, memory, and judgment. The underlying brain basis for these deleterious effects has been largely elusive. New findings published yesterday in Neuropsychology reveal that decreased connectivity between network-specific brain regions are to blame for the central deficit common to the various cognitive changes associated with MS, slowed cognitive speed.
In the first study of its kind, researchers at the Center for BrainHealth at The University of Texas at Dallas and The University of Texas Southwestern Medical Center found that, compared to healthy controls, individuals with MS exhibit weaker brain connections between the dorsolateral prefrontal cortex and posterior brain regions. The change amounts to a breakdown in communication between the part of the brain responsible for executing goal-directed thought and action and the regions responsible for carrying out tasks related to cognitive speed such as visual processing, motor execution, and object recognition. The researchers believe that the diminished connections are likely the result of decreased white matter surrounding the neurons in the brain.
"Our study is the first to really zero in on the physiology of cognitive speed, the central cognitive deficit in MS," explained Center for BrainHealth principal investigator Bart Rypma, Ph.D., who also holds the Meadows Foundation Chair at UT Dallas. "While white matter is essential to efficient network communication, white matter degradation is symptomatic of MS. This study really highlights how tightly coupled connectivity is to performance and illuminates the larger, emerging picture of white matter's importance in human cognitive performance."
Collaborating with Elliot Frohman, M.D., Ph.D., director of the Multiple Sclerosis Program and Clinical Center at UT Southwestern, the study recruited 29 participants with relapsing-remitting MS and 23 age- and sex- matched healthy controls. Participants underwent functional magnetic resonance imaging (fMRI) while completing a measure of cognitive processing speed. Participants were given 4 seconds to view a nine-item key of number and symbol pairs (for example '+' above the number 3) and one number-symbol pair probe. Participants were asked to indicate with a left or right thumb button press whether or not the probe appeared in the key.
While accuracy was similar for both healthy controls and individuals with MS, response times for individuals with MS were much slower. Analysis of the fMRI data revealed that while completing this measure, MS patients showed weaker functional connections with dorsolateral prefrontal cortex.
"These findings reveal a diffuse pattern of disconnectivity with executive areas of the brain," explained the study's lead author, Nicholas Hubbard, a doctoral candidate at the Center for BrainHealth working with Dr. Rypma. "Importantly, these decreases in connectivity predicted MS-related cognitive slowing both in and out of the fMRI environment suggesting that these results were not specific to our task, but rather were able to generalize to other situations where cognitive speed is required."
This research supports the need for therapies that target white matter structures and white matter proliferation. Rypma and Hubbard are currently conducting research to further explore the physiology of white matter to better understand cognitive speed reductions not only in MS, but also in healthy aging individuals.

MS Trial Alert: Researchers in California, Colorado, New Mexico and Pennsylvania Recruiting Women with Progressive or Relapsing MS for Study of Estriol to Improve Cognition

Summary: Investigators in California, Colorado, New Mexico and Pennsylvania are recruiting 64 women with MS relapsing-remitting, secondary-progressive, or primary-progressive for a 12-month study in which the sex hormone estriol will be compared with inactive placebo for effects on cognitive function. Participants can remain on their prescribed MS medication throughout the study. Rhonda Voskuhl, MD (University of California at Los Angeles) is the principal investigator of the trial. The study is funded by various private donors to the UCLA program.

Rationale: Estriol levels rise to very high levels naturally during late pregnancy, a time when most women’s MS disease activity declines. This led some to suspect that estriol may be responsible for this easing of symptoms during pregnancy. Dr. Rhonda Voskuhl (University of California, Los Angeles) and others showed that in mice estriol treatment was indeed protective. They then explored this lead with Society support, showing that estriol decreased disease activity in a small, early-phase trial of estriol in 12 women with MS. The National MS Society funded a team of investigators at 15 medical centers to conduct a two-year, controlled clinical trial of estriol added to standard therapy to treat MS. This trial recently reported results.

Meanwhile, Dr. Voskuhl’s team also has shown that, in mice, treatment with estrogen (a hormone related to estriol) can improve nerve impulse transmission in an area of the brain related to learning and memory, called the hippocampus. Problems with learning, memory and other cognitive functions are common in MS. (Laboratory Investigation 2012;92:1234) These and other observations led to the launch of this clinical trial to test the ability of estriol to improve cognition in women with MS.

Eligibility and Details: The researchers are seeking volunteers who are women 18 to 50 who have been diagnosed with relapsing-remitting, secondary-progressive, or primary-progressive MS. If participants are on standard MS treatments, they may remain on these medications during the study.  Participants should not have had a relapse within 30 days before the day of trial enrollment. A cognitive test called the Paced Auditory Serial Addition Test (PASAT) will be administered to determine whether the participant qualifies for the study. Participants are excluded if they are on oral contraceptives, hormone replacement therapy, progesterone IUDs or other sex hormones during screening and during the 12-month study period. For more details about enrollment criteria, please contact the site nearest you (listed below).

Participants are being randomly assigned to receive oral estrogen (8mg/day) or inactive placebo for one year. The primary outcome is improvement in cognitive function as measured by PASAT scores. Secondary outcomes under study include measurements from brain MRIs, cognition, quality of life, depression, and fatigue.

Contact: To learn more about the enrollment criteria for this study, and to find out if you are eligible to participate, please contact (for information about all sites nationwide):

University of California, Los Angeles
Contact: Jenny Bardens
Phone: (310) 206-2176
Email: jbardens@mednet.ucla.edu

Thinking Problems in People With Multiple Sclerosis

When you've got multiple sclerosis, losing your keys or forgetting a name can be scary. You wonder whether the illness is clouding your thinking.
It's true that over time, about half of people with MS can have some cognitive problems. That means poor focus, slowed thinking, or a fuzzy memory.
Often these problems are mild and don't really interrupt your daily life. It's pretty rare to have severe thinking problems. They affect about 5% to 10% of people with MS.

Signs of Impaired Thinking in MS

The clues that you have fuzzy thinking due to MS are often subtle. You might not notice them until a friend, co-worker, or family member points them out. You may:

• Struggle to find the right words to say
• Forget things you need to do or tasks already done
• Find it hard to plan or set priorities
• Have trouble concentrating, especially when two things are happening at once

MS usually does not hurt your intelligence or long-term memory. It won't change your ability to read or carry on a conversation.

Tests and Diagnosis for Impaired Thinking

If you suspect impaired thinking, talk with your neurologist or family doctor. Fuzzy thinking can have many causes.
Your doctor can make sure your problems don't come from normal aging or drugs that may cause confusion, depression, anxiety, or fatigue.
Once you have any health problems fully treated, the next step is usually testing. Your doctor may refer you to a neuropsychologist, speech pathologist, or occupational therapist.

MS and Rehab for Your Brain

If test results show that MS is to blame for spotty memory or poor mental focus, you may want to try rehab to sharpen your thinking. It can include:

• Memory exercises on a computer
• Home or work strategies with notebooks, organizers, or filing systems to help you remember things

It’s possible, but rare, that thinking problems become so severe that someone with MS needs constant care or can't live on their own. If this becomes an issue, discuss your options with your doctor and family. A social worker or psychologist also can help explore options for care.

Can Medicine Help?

Scientists are doing studies to see whether the drugs that slow the nerve damage in MS -- called disease-modifying medicines -- can help with thinking problems, too.
Others are looking at treatments, such as Alzheimer’s medications, that may temporarily improve your memory and focus. Ask your doctor to give you updates on any promising results.

From www.WebMD.com

Study in Pediatric MS Shows Racial Differences in Cognitive Impact

MS affects some cognitive functions more severely in black children than white children, according to newly published research from a team at the University of Alabama at Birmingham (UAB). The findings could help healthcare providers create individualized treatments for children suffering from the disease.

"We don't yet understand the biological reasons, but the bottom line is treatment options must be re-evaluated and be aggressive enough, especially with black patients, to prolong quality of life for as long as possible," says Kelly Ross, M.A, a psychology doctoral degree candidate in the UAB College of Arts and Sciences and lead author of the study.

Although MS in children is much less common than in adults, the disease may impact cognitive function more in younger people because their nervous systems still are developing.