Research Roundup

by Margaret Wahl

MDA to fast-track lithium trial

A small trial has suggested that lithium carbonate may dramatically slow ALS progression. Larger trials will be needed to confirm these results.

An MDA-supported clinical trial of lithium in ALS is being planned, after a 44-person study in Italy showed the drug delayed progression of the disease compared to a placebo (inactive substance).

“Although the number of study participants was small, the results are very intriguing,” said neurologist Valerie Cwik, MDA’s medical director and vice president of research. “MDA already is working with researchers in the United States to launch a larger, confirmatory study as quickly as possible.”

In the Italian study, 16 trial participants were randomly selected to receive riluzole plus two daily doses of lithium carbonate. The remaining 28 participants were randomly assigned to receive riluzole only. The two groups were matched for pulmonary function and percentage of people with bulbar-onset ALS.

After 15 months, about 30 percent of the patients who took riluzole alone had died, while all those receiving riluzole plus lithium had survived. The disease had progressed markedly in the riluzole-only group, but very slowly in the riluzole-plus-lithium group.

Francesco Fornai at the University of Pisa (Italy), with colleagues at other Italian institutions, announced the results online Feb. 4 in Proceedings of the National Academy of Sciences.

Lithium should be taken under a doctor’s supervision, with frequent monitoring of blood levels to check for toxicity.

[Note: Once MDA begins recruiting clinical trial participants, it will be announced in the newsmagazine and on the MDA ALS Web site.].

Arimoclomol trial on hold

On Jan. 22, the U.S. Food and Drug Administration (FDA) told CytRx Corp. not to proceed with the phase 3 trial of arimoclomol in ALS until the agency could further analyze previously completed animal studies with the drug.

For more, see www.cytrx.com.

Looking outside nerve cells for causes of ALS

Recent work by two scientific teams extends earlier findings that, while muscle-controlling nerve cells (motor neurons) are lost in ALS, other cells in the nervous system probably also play a role.

New research confirms that non-nerve cells in the nervous system are involved in at least one form of ALS. These might be easier than nerve cells to replace or support.

Investigators at the University of Iowa led by John Engelhardt have found that an abnormal protein that underlies a familial form of ALS can cause damage apart from anything it’s doing in motor neurons.

Engelhardt and colleagues found that in immune-system cells of the nervous system called microglia, the SOD1 protein normally interacts with a protein called RAC1. The SOD1-RAC1 complex then triggers a third protein, NOX2, to produce needed but potentially dangerous molecules called reactive oxygen species, or ROS, which can leak out and damage neighboring cells. They published their results online in the Journal of Clinical Investigation Jan. 24.

Normally, the SOD1-RAC1-NOX2 combination causes ROS production, but when these rise to a certain level, SOD1 and RAC1 separate, and ROS production stops.

“In essence, SOD1 acts like a thermostat, which senses ROS and tells the NOX2 complex when to stop producing ROS,” Engelhardt says.

But in mice with mutated SOD1 genes, SOD1 doesn’t separate from RAC1. The thermostat is broken, the furnace stays on, and toxic levels of ROS damage nearby cells, such as motor neurons.

When the scientists gave the chemical apocynin to 2-week-old mice with an SOD1 gene mutation, the animals had a more slowly progressing ALS-like disease and ended up with more spinal cord motor neurons than untreated mice did. Apocynin is a small chemical found in certain plants that interferes with production of ROS molecules by “unplugging” the molecular furnace. The mice received it in their drinking water.

A complementary study by scientists in the United States and Japan suggests targeting cells called astrocytes also might be beneficial.

Like microglia, astrocytes are in the nervous system but aren’t nerve cells (neurons). They normally support neurons by keeping their environment nontoxic.

Don Cleveland at the University of California-San Diego led a research team that included MDA grantee Severine Boillee at UCSD and published its findings online Feb. 3 in Nature Neuroscience.

When these investigators bred mice with diminished production of mutated SOD1 in their astrocytes alone, they observed sharply slowed disease progression compared to progression in mice that produced high levels of mutated SOD1 in these cells.

In areas where astrocyte-produced mutated SOD1 was high, microglia revved up production of toxic compounds.

In 2006, Boillee and colleagues showed that decreasing mutated SOD1 protein levels in microglia also sharply slowed disease progression in mice.

Genes involved in axon guidance implicated in ALS

Investigators at the Mayo Clinic in Rochester, Minn., and the University of Miami have applied a new approach to studying genetic variants that may play a role in ALS and say genes involved in “axon guidance” are significantly different in people with ALS, as compared to healthy subjects.

Axon guidance refers to the process by which the brain and spinal cord are “wired” during fetal development and the process by which this wiring is maintained and repaired throughout life.

Axons (nerve fibers) connect nerve cells to muscle fibers and to other nerve cells. They need maintenance throughout life.

Two previous analyses, called “whole-genome association” studies, compared all the DNA of a group of people with ALS to all the DNA of a group of people without ALS. The first study, which was MDA-supported and conducted by the Translational Genomics Research Institute in Phoenix, found some 50 variants that might contribute to ALS, including one that was particularly significant. (The function of the gene in which this variant was found has not yet been identified.)

The second study, conducted by the National Institutes of Health, found no significant DNA differences between the ALS-affected and unaffected groups.

In this new analysis, Demetrius Maraganore at the Mayo Clinic and colleagues, who published their findings in the January issue of PLoS One, hypothesized that genes involved in axon guidance might have ALS-associated variant DNA sequences.

When they looked at 128 genes already identified as being in the axon-guidance pathway and compared them as a group in the ALS-affected and unaffected study participants, they found a significant difference in the two types of participants.

MDA is talking with the Mayo Clinic group about pursuing this line of research.

XMRV not an ALS contributor

The so-called xenotropic MuLV-related virus (XMRV) has been eliminated as a contributor to ALS, according to Jeremy Garson at University College London (UK) Centre for Virology and colleagues.

The research team, which announced the findings in the Jan. 22 issue of Neurology, included Robert Brown, director of the MDA/ALS Center at Massachusetts General Hospital in Boston. When they searched for genetic material from XMRV in ALS patients’ blood, they found none.

The investigators say their results show that XMRV is highly unlikely to explain elevated levels of activity of the viral enzyme reverse transcriptase seen in ALS patients’ blood. They say they’ll continue to search for other viruses.

by Amy Labbe

Gae and Lauren Skager with their golden retriever puppy, Dakota, encourage people across the nation to organize ALS support groups for children and youth.

"ALS affects my life, too!” says 13-year-old Lauren Skager of Minneapolis.

Lauren’s mom, Gae, has ALS. Lauren sometimes translates for her, but more and more Gae uses her DynaVox communication device to speak. Lauren worries people will become impatient waiting for her mom to type out what she wants to say.

“I wish they could understand her like me,” Lauren says, noting that she feels “relieved” when her mom finishes typing her message and “an embarrassing incident is averted.”

Lauren’s worry is but a small example of the myriad ways ALS affects not only the individual but the entire family. To help children live full lives despite ALS worries, check out the following tips from the Skagers and other families touched by the disease.

Participate in a youth support group

Don’t overlook one-on-one or family counseling, but consider looking for a child/youth support group as well.

Justin Alderman with sisters Jessica, left, and Breanna, says “it’s OK to be a little worried” about a parent with ALS. “But don’t let it control you.”

Gae, who worked as a registered nurse prior to receiving her diagnosis, says children can gain significant benefit and support from talking with peers.

“Because this disease is so rare and devastating in its progression, children often feel isolated and alone in their emotional struggles,” she notes. Peers who also have a parent living with ALS (or other chronic conditions like cancer or multiple sclerosis) can provide insight to each other in coping with family changes.

Lauren participates in MDA’s Support Group for Children/Youth of ALS Patients in Minneapolis. Facilitated by a pediatric neurologist and attended by approximately nine children ages 10 to 17, the group meets bimonthly for 90 minutes.

Lauren says she enjoys going to the meetings and finds the sessions “interesting and very informational. It helps to know that other kids are coping with the same situation.”

Find support online

Support doesn’t have to be face-to-face; you can find it from the comfort of your living room with a click of the mouse.

As a teenager, Sarah Butler (now 21) of Tucson, Ariz., frequented Yahoo’s Living With ALS group. There she posted questions and stories, vented frustrations and made supportive friendships that helped her deal with her father’s ALS.

MDA offers several ALS-specific chats each week; go to www.mda.org/chat/calendar.html to see the schedule and sign up. The ALS Chat by ALS Forums can be found at www.alsforums.com.

Stay busy; have fun

Sean Dwyer, left, with father, Pat, and Brenna Dwyer, below, find numerous ways to enjoy the present and focus on the positive things in their lives.

School activities, hobbies, pets and part-time jobs all serve as outlets and touchstones for kids and teens.

Brenna Dwyer, 18, and Sean Dwyer, 16, of Kenmore, Wash., say their activities have helped them deal with their father Pat’s ALS.

Brenna, a high-school senior, particularly enjoys horseback riding. She says her horse, Bailey, always has been her “shrink” and that when she rides she’s unable to think of anything else.

“Whenever my mind does wander off, she’s smart and sensitive enough to let me know that she’s the one I need to be paying attention to,” Brenna says.

Sean, a sophomore, plays drums in a band, plays basketball, skis and makes movies of his friends skiing. He also enjoys spending time with his dad rebuilding a vintage Triumph TR-6 convertible.

“What I do to not worry as much is to just live life in the present and take advantage of every moment that I have with my dad,” Sean says. “I just try to have so much fun and to be so content that I just forget about all the bad things.”

Learn and teach about ALS

Knowledge often inspires a sense of empowerment, and children who learn about ALS find themselves in the unique position of being able to educate others about the disease, both by sharing what they’ve learned and by demonstrating it’s nothing to be embarrassed about.

Breanna Alderman, 17, of South Jordan, Utah, won a trophy in an essay contest when she was in the sixth grade, after writing an essay about her father Alan’s courage in facing ALS.

She says at first, however, she was ashamed of ALS and what it was doing to her dad.

“After awhile I realized that there was nothing we could do about it, so I might as well learn from it,” Breanna says. “So, I try and teach other people about the disability and other [disabilities] like it.”

When her friends come over, Breanna tells them it’s OK to talk to her dad and explains to them about the disease.

Alan says Breanna and her younger brother and sister, Justin, 15, and Jessica, 11, are quick to stick up for him and for others with disabilities. Most of all, though, he says they show others that ALS is nothing to be embarrassed or ashamed about by continuing to “excel and go on with their lives.”

Communicate and engage

Open all lines of communication and stay involved.

Alan Alderman and his wife, Shaun, find support in their extended family and church group, and Alan notes, “When I was first diagnosed we also met with all of our children’s teachers, coaches, dance and music instructors, and others that associated with our children to make them aware of the situation and to ask for their help in watching out for our kids.”

The Aldermans also have family meetings to discuss Alan’s condition, where he says they openly discuss what’s going to happen and “encourage their questions.”

Alan advises parents, “Don’t let ALS be the reason for doing, or not doing, things.

“Continue to be engaged and involved in their lives as much and as long as you can. And love them! Express that love often and unconditionally.”

ALS and Vets: Searching for Connections

by Bill Norman

Army Ranger veteran Beau MacVane, battling ALS, works out daily on his trike, and with special lines constructed in his back yard.

Statistics confirm that ALS strikes U.S. military veterans more frequently than it does the general population. One study conducted in 2005 found that veterans, regardless of when they served, are 60 percent more likely to contract ALS than people who were not in the military.

Even among vets, however, some groups are more prone to get the disease than others. In particular, those who served in the first Gulf War, August 1990 to February 1991, are nearly twice as apt to contract ALS as veterans of other conflicts.

Why? Nerve gas or other weapons-related toxins? Combinations of chemicals in the bloodstream from all the inoculations troops received?

Unfortunately, as with ALS in all of its contexts, there are no clear-cut answers. Yet.

Nerve gas, pesticides and enzymes

Returning from the Gulf War, some veterans complained of assorted ills that included loss of coordination, numbness in the extremities, constant pain and impaired thinking.

The Department of Veterans Affairs under the Clinton administration dismissed those complaints as the result of stress (neurotic vs. neurologic).

But in 1997, physician-epidemiologist (and specialist in Gulf War syndromes) Robert Haley and researchers at the University of Texas Southwestern Medical Center in Dallas found that several influences were associated with neurologic symptoms similar to those reported earlier by veterans.

Symptom similarities

Haley categorized those symptoms as lack of coordination, joint, muscle or nerve abnormalities and impaired thinking.

The influences associated with the symptoms included nerve gas, the medication given to counteract the effects of the gas, and several types of pesticides, including the one used in flea collars (which some soldiers wore to kill sand fleas).

In 1999, Haley and researchers at the University of Michigan published findings that linked “Gulf War syndromes” to sluggish activity of an enzyme called PON1. This enzyme helps detoxify nerve gas, anti-nerve gas medication, pesticides and insect repellents.

Researchers drew blood from 26 veterans affected by Gulf War syndrome and 20 who were unaffected. The affected group also reported exposure to nerve gas and/or pesticides, and severe negative reactions to anti-nerve gas medication.

The findings: Blood from affected vets showed low PON1 activity and the substitution of one amino acid molecule (arginine) for another (glutamine) in the enzyme — both associated with the development of abnormal neurologic symptoms.

In some cases, years later, vets who had manifested these symptoms developed ALS.

Haley theorizes that if researchers can increase the level of PON1 activity in humans (they’ve done so already in rats), they may be able to mitigate or negate the effects of some substances like nerve gas.

In the interim, thousands who fought one war only to face another when they returned home, are anxiously waiting.

A tale of two vets

Bob Bischoff

Beau MacVane

Bob Bischoff and Beau MacVane are worlds apart in age and distance. Their common characteristics are that they’re both military veterans and have ALS. Yet their years in the military reflect markedly different experiences and exposure to influences that may or may not have contributed.

MacVane has had ALS for slightly more than a year, Bischoff for eight years.

Once a 10 handicapper

Bischoff is 73. He served in the military from 1954 to 1956 as a radar technician, just as the Korean War was winding down, and then as an electronics technician for eight years after his discharge. For another 15 years, he worked as a land surveyor at an oil refinery near his present home in El Dorado, Kan.

The exposure to electronic fields and petroleum refining are the only things he thinks could even remotely be connected to his ALS, and even so, he didn’t begin experiencing symptoms of the disease until 2000.

At the start of that year he was a serious and proficient golfer. In 2001 he played his last game. “I fell down every time I swung the club,” he said. “I just couldn’t do it anymore.”

Now Bischoff requires a caregiver 24/7 and uses a power wheelchair with sip-and-puff controls. He cruises the Internet and exchanges e-mails with the aid of a silver sequin affixed to the middle of his forehead. By reflecting light off the sequin onto a special keyboard mounted atop his computer monitor, he can “type” characters and activate command keys.

A Wichita television station devoted an hour to the subject of vets with ALS, and Bischoff was interviewed extensively. The American Legion post in El Dorado honored him recently for his years of supporting the group’s golf, bingo and finance committees.

Bischoff feels very strongly that getting the word out about ALS and its toll on vets will focus public attention on the issue and finally help identify causes and treatments.

Always a hard charger

Beau MacVane played five years of college football and then served five tours of combat duty in Afghanistan and Iraq from 2002 to 2006.

An Army Ranger (specialized airborne infantry) with a chest full of campaign ribbons and unit citations, he saw action in some of the hottest war zones.

His first intimation that something might be wrong occurred while he was still in the service and began experiencing hoarseness in his throat. Discharged in 2006, he received his ALS diagnosis in April 2007. Now 31, he lives with his parents in Boca Raton, Fla. His mother, Sandi, calls his present battle “the war after the war.”

MacVane can’t think of any particular influences in the military that connect to ALS, although he says the Veterans Administration has told him it’s due to some type of toxin. He recalls walking through areas where Iraqi munitions and shell fragments were scattered, and wonders about the shots he and other troops received to counter the effects of nerve gas.

Otherwise, he says, “We were just ordinary people doing extraordinary jobs — jobs that had more peculiarities than civilians are exposed to.”

MacVane can walk carefully with the aid of a staff. He walks and works out daily on a recumbent bicycle. He has an athlete’s physique and a steely spirit.

“We’re all just staying the course until a cure can be found,” his mom says. “Beau makes projects happen in order to keep busy [he just completed building a 240-gallon aquarium], but his mind is totally focused on beating this thing.”

Let Your Feet Do the Talking
Foot controls open doors for computer access

by Alyssa Quintero

Augie Nieto’s large trackball mouse helps him communicate extensively with family, friends and colleagues.

Severe hand and arm weakness can make using a conventional computer keyboard and mouse impossible. Eye-tracking and head mouse technology can help, but if you have adequate lower-body strength, it may be worth letting your feet give you a hand.

Foot controls — including trackball and rollerball mice, programmable foot pedals and foot switches — offer viable options for maintaining computer access.

Trackball wizard

Augie Nieto, MDA’s ALS Division co-chairperson and the driving force behind MDA’s Augie’s Quest research initiative, spends much of his day on the computer, communicating with people around the globe.

Since his diagnosis in March 2005, the disease has affected his upper body strength and speech, leaving him unable to grip his computer mouse. So in April 2006, he placed his large, yellow trackball mouse on the floor and started typing with his feet.

“It wasn’t difficult at all,” Nieto, 50, said via e-mail. “For me the ability to continue communicating is key as my voice deteriorates. I’d definitely recommend this to other people with ALS.”

Nieto currently types 50 words per minute using his foot mouse. He uses his left foot for “clicks” via a blue button switch, and his right foot to type and move the 3-inch BIGtrack trackball mouse ($79, Infogrip, see “Resources”).

In conjunction with the foot mouse, Nieto uses the Dasher program to type e-mails and other documents. Dasher is a text-entry interface that’s operated by continuous pointing gestures. The user chooses what to write by choosing where to zoom.

On Nieto’s flat-screen monitor, letters and colored boxes scroll up. Moving the mouse with his feet, he selects letters and phrases, which then move to the left side of the screen until whole words, phrases and sentences appear. Created by a team of physicists at Cambridge University in England, Dasher has such built-in energy-saving features as word completion and the ability to learn commonly used words.

“Using the foot mouse and the Dasher program is inexpensive and very easy to learn,” Nieto added. It took him a week to master the program, which can be downloaded at no charge at www.inference.phy.cam.ac.uk/dasher.

Feet pave the way

By the time Bert Woodard of Satsuma, Ala., received his first computer in 1999 — 16 years after his ALS diagnosis — he’d already lost the use of his arms and hands, so he started off typing with his feet.

In the beginning, Woodard, now 50, typed on an oversize keyboard with a pencil and eraser topper strapped to his right foot, while his left foot maneuvered the trackball and moved the cursor. In fact, Woodard wrote most of his book, Living With It, Not Dying of It (Westview Publishing Inc., 2007), by using this method.

As his ALS progressed, Woodard began using the foot mouse to move the cursor and type via OnScreen with Word-Complete ($99-$119), an on-screen keyboard he purchased from EnableMart (see “Resources”).

Bert Woodard learned to use his first computer by controlling it with his feet.

“With ALS, if you have a body part that still works, use it,” he wrote via e-mail.

Woodard, who spends about seven hours each day at his computer, now uses a smaller trackball called Marble Mouse ($19.95, Logitech, www.logitech.com). He was having difficulty using the large yellow trackball because his foot often slid across it without making it move. It also got in his way, preventing him from pressing the left click button to make selections.

“I like the smaller rollerball/trackball mouse because your foot can cover the ball, and move to the right and left click buttons more easily. Most importantly, you don’t have to keep moving your leg up and down, which can be tiring,” he explained.

Foot and mouth

Dov Wisebrod of Toronto, Ontario, Canada, uses his computer as his speech-generating device.

Because he has only slight movement in his face and left big toe, Wisebrod employs a toe switch and a single-switch scanning method to maintain communication. (“Switch scanning” scans through various options, displaying them sequentially on the screen. The user clicks the switch when the desired option is highlighted.)

“Maintaining the ability to have a conversation and interact socially is vital to the quality of my life as my body deteriorates,” Wisebrod, 35, said via e-mail.

Wisebrod tapes the switch to the top of his toe because he can move it thousands of times a day with reliable precision. He uses the Sensor Switch Kit ($149.95, Enabling Devices, www.enablingdevices.com), which is connected to the computer by a USB switch interface called Swifty ($79.95, Origin Instruments, www.orin.com).

Dov Wisebrod’s toe switch method is a prime example of doing whatever it takes to stay online.

The blue sensor switch is sensitive to bending and vibration, so when Wisebrod bends his toe, a signal is sent from the switch to the interface, which translates the signal into a left mouse click and activates the switch-scanning selection options. Wisebrod, who learned he had ALS in 1994 while attending law school, was dissatisfied with other scanning software, so he developed the Skeleton Key on-screen keyboard (www.myskeletonkey.com).

“Although scanning in Skeleton Key can be controlled by either one or two switches, I use only one due to the difficulty of precisely positioning a blue sensor so it works properly,” Wisebrod said via e-mail.

He noted that his feet have become his pathway to expression. “Even with the limitations of scanning, I can control all of my computer’s keyboard, mouse, text-to-speech, software and other powerful functions.”