R U A WARE?

It's ALS Awareness Month. As per usual, certain advocacy agencies are content with passive website pages and extolling their constituents to do the heavy lifting of spreading the word (a practice that has dramatic fall-off beyond the tiny individual circles of family and close friends). The agencies bleed enough contributions from the constituency to pay salaries and provide token services (with no consistency between Chapters). Meanwhile, The general public is still unaware and uninformed about the deadly lottery that is ALS.

Up until very recently, ALS was a disease of silence. As Person(s) with ALS (PALS) progressed, they lost their abilities to communicate and mingle in their communities. Very quickly they were shut away in homes or hospitals to die in mute angst with a capable mind trapped in an inert body.

With the advent of social media, as well as the technology of mobile computers with eye-tracking input systems and text-to-speech synthesis, PALS are able to compete on an even footing in cyberspace with more physically capable people. Many of these PALS are in serious medical conditions such as near total paralysis with some on mechanical ventilation via tracheotomy. As the astrophysicist and PALS Stephen Hawking said, "My body may be crippled but my mind is free." Tech-savvy PALS are able to use combinations of technology to dramatically increase their standard of living, to contribute to research about the disease, and even band together to lobby government to speed up access to promising pharmaceuticals. As wonderfully-explained in a recent forbes.com article, "Technology is the cure" (thanks to Steve Saling for coining that phrase).

On a personal note, technology is saving my life. Many years ago my father was in the US Air Force flying support missions for the Apollo moon flights. On occasion I would be in ARIA control watching technicians tending to walls of huge computers. I thought that was the neatest thing ever. Years later, I was blessed to turn a childhood hobby (began when I commandeered my dad's IBM PC in 1980) into my career, and I now have in front of me more computing power than all the Apollo vehicles combined.

When I was diagnosed, I knew that my ability to communicate was going to disappear. Knowing that hands-free computer technology existed, and already having a long-term presence in "cyberspace", I knew that I would be able to be social and productive as my physical ability declined. This was paramount in my decision to accept mechanical ventilation. Without the ability for my mind to escape my physical confinement, I would have years ago allowed myself to succumb to ALS. Instead I have remained active and have had the extraordinary privilege to meet and participate in the global ALS Community.

Unsatisfied with the level of advocacy and awareness generated by organizations with that as their claimed mission, PALS in the global ALS Community are taking it upon themselves to increase awareness and advocacy, and are placing pressure on those representative organizations to change old operating procedures. Other organizations representing other medical conditions are very vocal and aggressive in public awareness (the foundation of funding and national priority for research) and this new group of PALS demand commensurate action from the organizations representing them. The new computer technologies, mobile devices with apps, and ubiquitous connection to the Internet and social media allows PALS to congregate, exchange ideas, and mobilize. No longer are they shut away and forgotten.

This month, are aware or are you just a ware for fundraising that does little?

Lack of Inhibition

ALS is frequently regarded as a disease just of the motor cortex, but degeneration is also seen presymptomatically in other cortical areas with functional connectivity to the motor cortex. It seems that the areas of highest functional connectivity overlapped with areas of highest damage. This is theorized by researchers to be due to a loss of certain neurons which serve to modulate the activity of other neurons ("inhibitory neurons") in a process called "cortical hyperexcitability". In a recent study, researchers measured levels of GABA to support the evidence of this process in PALS. In a similar study published 04-18-2012, GABA was also found decreased in the motor cortex of PALS vs healthy control subjects.
Emerging evidence in another neurodegenerative disease, Alzheimer's Disease (AD), indicates a similar functional connectivity method of progression. In another more recent study this was also linked to a similar-sounding process called "network hypersynchrony".

Under Press-Sure

Over the past two weeks ALS has gotten some much-needed national coverage, first from the Wall Street Journal followed shortly by ABC News. I also just completed the first round of questions for an article due to appear in July in the-scientist.com. More opportunities seem to be materializing and I will do my best to keep the momentum going to keep the message of ALS in front of the public. I would like to call upon everyone to contact their local press, mention the WSJ and ABC News articles, and tell them YOUR stories. If you think it would help to mention a relationship to me, do so and I will back you.

There were a few points in the articles that I wanted to clarify:

• I did not design the computer I use. It is a TabletKiosk Sahara Slate PC i440T with a Point Grey Flea-2 CCD camera with an infrared light and lense. The system uses the ERICA software made by Eye Response Technologies (since purchased by DynaVox). The only part of the computer I modified was my work environment and I installed certain programs and utilities which I use. I did help design the overhead mount which slides along the overhead track I use for my lift.
• NP001 is indeed sodium chlorite, but when ingested orally the acid in the stomach breaks down most of it. The most optimistic data I have seen (based on rats exposed to it in drinking water) is a maximum 30% reaching the bloodstream. I would expect that to be less, and to be variable, in most people.
• Because NP001 is already in clinical trial, I arranged the project more as an "early access" model with data-keeping as secondary.
• I have three criteria for any such projects:
  • drug must be relatively safe
  • drug must be inexpensive
  • drug must be legal to obtain

It's very important to me that I don't recklessly put other PALS in physical, financial, or legal jeopardy with any project. My intention is to help not harm. We all already have enough problems to deal with.

Old Tricks

Something very intriguing came in over the weekend from PLoSONE. It was a study comparing neuromuscular junctions between age and ALS. It turns out that the same muscles susceptible to denervation in ALS are likewise susceptible to denervation with age. Autonomic muscles (those that act without your conscious input) and muscles innervated directly from the brain (eg your eyes and certain facial muscles) are extraordinarily resistant to age- and ALS-related denervation. Something that struck me was the finding that TDP43 was mislocalized in aged motor neurons very similarly to ALS motor neurons. TDP43 is normally found in the nucleus but in ALS it is found in the cytoplasm where it is cleaved by caspases and a 25 kilodalton fragment aggregates in a form that apparently gains a toxic function.

TDP43 mislocalization has also been found by the symptomatic phase in the SOD1 mouse model (although earlier and more recent reports are somewhat contradictory on this point). Another protein found upregulated in the SOD1 mouse is CRMP4a, a subprotien of the CRMP family. CRMP4 is normally involved in learning, neurite outgrowth, and building functional circuitry within the brain. However, the Duplan, et al., 2010 study referenced above found upregulation or overexpression of CRMP4a is deadly specific to motor neurons. In the subject study of this post, Valdez, et al., 2012, CRMP4a was also found upregulated in the same types of motor neurons of normally-aged mice as those which degenerate in ALS mice. CRMPs are known to change due to age.

Inflammation is present in all neurodegenerative diseases. One of the primary drivers of ALS is thought to be neuroinflammation. Multiple animal models of ALS, including data in humans, show neuroinflammation. As the subject study shows, TDP43 and CRMP4 is upregulated in both aging and ALS. Taking one step further, aging and ALS have another thing in common: Inflammation.

Growth Potential

Two new studies came out that I found rather interesting. The ability to transfer into humans is years off but the progress is still impressive. First up, a team at the University of Toronto developed a new technique to expand stem cells at industrial capacity. Second, Children's Hospital of Philadelphia generated a new human stem cell type called an "endodermal precursor". If the new stem cell technique can also be used to generate ectodermal precursors, it could be a major advancement in regenerative therapy for ALS. Many additional steps would still be necessary but mass-production of teratoma-free cells would be an important contribution.

Letter From The Void

This letter was written in 2010 by another PALS who has since passed. I didn't always agree with him about certain things, but on this we most definitely do: ALSA National is letting us down. They have a nonexistent communication campaign unless it is to beg money from PALS (people already under severe financial stress). They have a basic research program that receives a small portion of the budget and no translational program (to move prospective drugs from the lab to the patient). They purport to provide equipment and services yet quietly refer people to other organizations because they "just don't do that". PALS may have good experience with their local Chapter (the OT in mine is an absolute superwoman) but there is no consistency between each Chapter.

This letter was written in 2010 and is unfortunately still true. ALSA is failing us.

Ms. Jane Gilbert,
I am writing to you as a 48 year old former airline pilot and victim of ALS, now in my fourth year. The purpose of this communication is to convey my terrible disappointment with the performance of the ALS Association at the national level. In my view, ALSA national is not putting the best interest of the patient community first. The game of baseball provides an excellent visual model of the awareness, advocacy, and research dynamics. Awareness is first base, advocacy is second base, research is third base, and a TRULY effective treatment resides on home base. Sadly, although the game has been playing for decades, the patient community has yet to reach first base. We have no unified national voice and no public awareness program. ALSA seems content to send e-mails to the patient community encouraging the purchase of cheap Chinese bracelets and have this serve as a national awareness program, which it clearly is not. The bedrock of an effective national awareness program is a series of public service announcements airing consistently on national networks. Anything less is a waste of time and resources. Here is what I can see during a typical day of television viewing. See if you can discover a pattern. Quite often on ABC at 6:45pm, I see an excellent PSA from the Alzheimer's Association, nothing from ALSA. I see KFC commercials for the "pink bucket" of chicken to support breast cancer initiatives, nothing from ALSA. I see PSAs for the breast cancer walk in DC on May 9th, nothing from ALSA. I see the PSA for the MS walk,nothing from ALSA. I see a PSA for the Epilepsy walk, nothing from ALSA. Earlier this year I saw yogurt commercials highlighting the "pink cap" for breast cancer, nothing from ALSA. Do you see the clear pattern that quickly emerges, Ms. Gilbert? Is this disservice to the patient community something to be proud of? ALS continues to be one of the best kept secrets in America because our national organization stubbornly refuses to initiate a consistent program of FREE public service announcements. Can you explain why ALSA refuses to place PSAs on national television? ALS Canada sets a fine example with their public awareness program, that includes an excellent PSA depicting all the phases of ALS in just a few seconds. After their PSA aired for a while, ALS Canada was pleased to notice a large increase in revenue. The PSA system is proven to increase awareness and donations, but it will not work if ALSA refuses to use it at the national level. Considering the bleak prognosis of the patient group, we need the loudest, most radical national organization to push progressive change. Anything less is a disservice to the ALS community. Because there is no national awareness program, and we haven't reached first base, advocacy is suffering on second base. An effective advocacy program depends upon an effective public awareness program. The public must know the details of ALS in order to support our cause. Likewise for those who control the federal research funds. A new phrase has been circulating on ALS blogs and forums. Anemic Advocacy. The sole use of this new phrase is to describe the advocacy of ALSA at the national level. Last year, we went to the Hill with tin cans to beg for only 5 million dollars from the DOD. This year we are asked to again approach the Hill for only 15 million dollars. While other patient groups demand adequate funding, we are encouraged to move in and sweep up the crumbs. Do you realize that even in 2001, HIV research was supported by 4 billion federal dollars? This year, the Alzheimer's Association is demanding 2 billion dollars. ALSA acknowledges that 95% of ALS research projects will go unfunded. This would not be the case if ALSA demanded real money instead of pocket change. This year, I will spend my time at the Missing Parts display. I will not carry the can to beg for table scraps. I will however, be willing to climb the Hill to demand not less than 250 million dollars in federal research funding. Swift access to investigational new drugs was a listed legislative priority in 2005 and 2006. Now that important priority is gone, and we still cannot access new drugs. When I asked ALSA for help with obtaining Iplex last summer, there was no interest. Why?I realize that ALSA may not be able to correct the many deficiencies in the research community, so I'll not dwell long on the third base of the model. Increased funding will help, as will increased communication between all research efforts. A major victory would be achieved if the conventional clinical trial structure were overhauled to reflect the reality of a fast moving condition such as ALS. The process must be simplified and streamlined. When patients don't live long enough to complete a trial, something is wrong. Just a few more concerns left. I know that a letter was sent to ALSA national some weeks ago asking that all organizations involved in the fight against ALS be welcomed to present at Advocacy Days. The request was denied. As a result, other fine organizations are forced to use the lobby or other hotels. Why is ALSA national so hostile to other organizations that just want to help? We need a unified effort, not political turf wars. What is the issue with signs this year? Last year, my daughter and I carried signs to increase ALS awareness and inform the public of our plight. The signs were very effective and well received at the conference, among the public, and on the Hill. Without signs, you can only bring the message to people next to you, if you still have a voice. You may know that many ALS patients lose their voice, therefor signs are the only means of personal expression and communication. With a sign, I can reach every person within 50' of my chair. I don't appreciate being lied to. ALSA seeks to prohibit free speech citing existing regulations prohibiting signs on the hotel property. Quick communication with the JW Marriott reveals that there is no regulation against signs. The element of trust has been damaged. I will once again bring my signs to communicate with the people. I do not wish to cause a disruption and I ask that ALSA not instigate a confrontation by attempting to take my voice away. I notice that the schedule is open on Sunday until 2 pm. Why are our veterans not being honored with a wreath this year?This is a public letter published on ALS forums. I challenge you to take the stage on Monday morning. Many within the ALS patient community will be interested in what you have to say.

The Mito-Can't-Rias

One of the earliest observations in ALS is a weakening of the energy-producing organelles of the cell called mitochondria. The mitochondria are found to only output about half of the energy as normal while producing more waste in the form of Reactive Oxygen Species (ROS). Think of your car engine horribly out of tune where you don't get your normal acceleration and nasty black smoke pours out of your tailpipe which causes you to fail smog inspection, only this smoke causes your car to rust away from the inside out. In addition to reduced energy output, mitochondria in neurodegenerative diseases also don't repair themselves well and have, in previous research, suffered from axonal transport problems which appeared linked to the "die-back" of the axon and detachment from the neuromuscular junction (NMJ).

However, a recent study that used live imaging of mouse motor neurons showed that axonal transport was independent of mitochondrial density and axonal degeneration. In mice with different SOD1 mutations, axonal transport was affected differently (or not at all). The motor neurons of the mice bred to have the SOD1 G93A mutation, which are used in the majority of studies because they are the model most understood, showed extensive axonal transport problems early on while G85R motor neurons showed very little even up to end-stage. Even mice bred to overexpress (multiple copies of the gene) human wild-type (non-mutant) SOD1 showed axonal transport issues without motor neuron degeneration. The "code" for the mutations refer to nucleotide transpositions at numbered locations in the SOD1 gene that creates the SOD1 protein. Below you can see movies of transport in the various types of neurons relative to controls.

WT-SOD1

G93A-SOD1

WT-SOD1

G85R-SOD1

WT-SOD1

WT-SOD1 (human, overexpressed)

I have previously posted about the role of mitochondria in ALS and discussed various implications. I have also posted about the possibility of a role of SOD1 in both FALS and SALS as well as the possibility of SOD1 as a prion in the propagation of ALS. In all the mutant SOD1, mitochondria show dysfunction early. Mitochondria also have "communication" with the Schwann cells at the NMJ which is an early event in the destruction of the NMJ and commencement of the axonal die-back.

Nothing is as simple as we would like, and ALS exemplifies this axiom. What would seem apparently causal might merely suggest another, as yet undiscovered, mechanism which may underlie other related observed effects. And sometimes what appears to be a related effect may just be something separate. Regardless of any doubt cast on the role of axonal transport in ALS, the mitochondrial dysfunction with which it is associated still appears strongly implicated. The cause of that remains under investigation.