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In most neurodegenerative disease of "older folks", there is neuroinflammation and formation of aggregates. Also, most such disease is sporadic, not directly inherited through a single genetic defect.

Most such neurodegenerative disease progresses slowly, with life expectancy from first symptoms greater than 5-10 years unless something else gets ya first.

Textbook classic ALS is rather different-- rapid decline with death or mechanical life support intervention occurring within 3 years of first symptoms. The single most common anecdote is "a year ago I was running marathons! now I'm in a wheelchair, what happened?" ALS has gotta be the only disease known to humankind where that's the single most common anecdote.

I'm not saying that all ALS is of the textbook classic kind, or that all fast progressors are athletes. ALS is not a specific disease, it's a diagnostic garbage dump. What I'm trying to do here is some diagnostic triage, and then speculate on what it means for therapeutic intervention.


I've been advocating this theory ever since I went public 8 years ago, because I was a fast progressor, a textbook sporadic case although not an athlete. Here goes again, with some things I've learned in the intervening 9 years.

1. Something happens to provoke neuroinflammation.

2. Neuroinflammatory conditions are fairly common among older folk, but the inflammatory process usually doesn't go berserk. It just kinda chugs along at a fast idle in first gear, slow but relentless.

3. In classic ALS, stressed motor neurons release molecular signals that tell the immune system that there's trouble. The immune system thinks there's an infection (and maybe there actually is!) and decides to put the stressed motor neuron out of its misery.

4. Now the motor neuron is dying, releasing more molecular signals indicating trouble. The immune system sends in the cleanup crew to mop up the crime scene.

5. The cleanup crew themselves are messy, scattering bits and pieces of garbage and throwing their cigar butts on the ground.

6. The remaining motor neurons are now having to carry a heavier electrical load, meanwhile they're already stressed by whatever the original stress was and additionally stressed by the toxins released by the damage control crews.

7. It's now an apoptotic cascade. It will only slow down when the body has so few motor neurons left that the immune system loses interest.

* * * * *

The most important "take this home" point in the above theory, is that in the initial stages, before the neurodegenerative cascade is being driven by apoptosis, in principle the disease could be cured with sufficiently aggressive anti-inflammatory therapy. The clinical problem is that by the time the patient has the diagnosis, the apoptotic cascade is usually well underway. Even if the apoptotic cascade isn't driving the process yet, neither the patient nor the neurologist have a clue how to treat what's in front of them, so it's going to progress to apoptotic cascade anyhow.

I'm gonna repeat the foregoing in different words. With early diagnosis and anti-inflammatory therapy, it may be possible to literally cure the disease.

The problems are:

1. Early diagnosis is rare.

2. Early anti-inflammatory therapeutic intervention doesn't happen: the patient doesn't know what's going on and the neurologist performs the riluzole maneuver, not the curcumin maneuver.

3. The patient was predisposed for unknown reasons to develop ALS. So, if it's cured, it's probably coming back.

The scenario I've just described is based on my own experience. Fast progressor, I figured out the Dx before the neurologists did, began a therapeutic regime that included anti-inflammatories as well as other magic stuff like zinc, was cured although with a bit of residual damage, but an unknown neurodegenerative process eventually overtook the healing processes and now it's a slow downhill slide. The cascade could kick in again at any time: a year ago I thought it had, but in the meantime the therapeutic interventions got better and I'm no worse off than I was a year ago.


By definition, classic ALS includes both upper and lower motor neuron involvement. There is abundant (if not conclusive) evidence that the disease begins with the lower motor neurons. But by the time you're in a neurologist's office, there's upper motor neuron involvement as well. Supposedly: more on that sarcastic comment later.

There's a dogma floating around in neurological circles that by the time you have LMN symptoms, half your LMN's are already dead ducks. I call malarkey on that play. With half your LMN's being dead ducks, your EMG would be replete with GMU's and your remaining motor neurons would be both diseased and overworked. And motor units that hadn't been commandeered by an adjacent motor unit wouldn't be working at all. We're not talking an athlete sagging a little off-peak, we're talking stuff a couch spud would be complaining about.

In the ALS continuum, LMN disease is associated with fast progression, and UMN disease is associated with slow progression. Let's split 'em up.

Lower motor neurons are busy suckers. Not only do they have to respond to UMN commands, they also have to reflex arc commands. The latter probably do 90% of the electrical work involved in a simple task like standing without falling. The reflex arcs are busy suckers because the time it takes for an action potential to get from your brain to your legs is longer than the time it takes for you to lurch into a nonrecoverable headbash. Reflex arcs may not be very smart, but at least they're quick.

Reflex arcs are mediated through those unsung heroes of the ventral horn that gets scarred in ALS, "spinal ganglia".

The popular picture of UMN and LMN is that there's this UMN that begins in the homunculus of the cerebral cortex where you think a think what ya want move, the signal goes down the spine to where that particular UMN mates up to its unique LMN, and from there the message goes to the neuromuscular junction. That popular picture is malarkey. The ganglia are little localized brains that process signals from multiple neurons including sensory neurons. Touch a hot stove? Your fingers were already pulling away before your brain felt the ouch. What is "lateral sclerosis"? Its the scar tissue that replaces dead ganglia.

Your brain doesn't know the details of how to stand up. It wouldn't do your brain any good to know, because you can fall faster than you can think. Besides which, when you're standing, wouldn't you like to be able to concentrate on something other than just how to keep from falling? Normal folks stand without giving the matter a second thought, it's all automatic. The lower motor neurons meanwhile are very busy!

I propose that that's why in ALS, LMD is the biggie. The lower motor neurons are the horses constantly being flogged, and when they slow down their buddies get flogged even harder. Once it's in neurodegenerative cascade, it's almost impossible to stop.

For any therapeutic regime to take a big chunk out of ALS, it has to stop the neurodegenerative cascade of lower motor neurons while it's still possible to preserve the function of the remaining LMN's despite the fact they're being hammered. In other words, the LMN's need more than a halt to the apoptotic cascade, they need some help to handle the additional load they're being subjected to. Otherwise it's all right back where it began.


It's quackery.

UMN is diagnosed on the basis of hyperreflexia and spasticity, on the theory that impairment of the inhibitory UMN's leaves the LMN's open to excessive stimulation by reflex arc sensory neurons.

This theory says nothing about the excitatory function of UMN's, their most obvious job (!), nor does it say anything about how spinal ganglia "micro-brains" work. It doesn't even consider the possibility that sensory neurons associated with their respective LMN's may be overexcited by the same disease processes that are afflicting the LMN's.

Let me simplify that. If you accept that LMN disease drives classic ALS, then the diagnostic criteria for so-called UMN involvement provide better evidence for involvement of the reflex arc (inclusive of sensory neurons and the spinal ganglia) than of UMN's.

The neurological community has long (if not universally) argued that so-called "Primary Lateral Sclerosis" (a slow UMN disease) is something distinct from ALS, whatever ALS is. As a minimum, ALS is typically driven by LMN disease in a big hurry.

For the sake of argument at the moment, I'll agree with them. PLS is an UMD disease that isn't driven into apoptotic cascade, which eventually afflicts the spinal ganglia leading to LMN involvement. Classic ALS on the other hand is a LMN disease which damages the spinal ganglia, leading to so-called "upper motor neuron symptoms" even though there is no significant involvement at the homunculus. If the upper motor neuron has problems, it's at the bus terminal in the ventral horn. The ticket agent has Alzheimer's.

To my knowledge, there is no evidence of primary accelerated neurodegeneration of UMN's in ALS, whatever neurodegeneration may be present is secondary to LMN apoptotic cascade damaging the terminus of the UMN.

********** PRIMARY LATERAL SCLEROSIS ************

The foregoing is my theory de jour of PLS. It's a theory that says the mainstream neurologist community got it right. How often do I say that?



These are subjects I haven't studied much because I don't have these symptoms myself. But, I'll give 'em a shot.

To my knowledge, pseudobulbar symptoms are never the first. Other symptoms come first. If someone with better information can contradict this, please do so. If you want to talk about the length of neurons, upper and lower motor neurons are long, long, jobbies with serious axon transport issues. If it's true that pseudobulbar symptoms are never the first in an ALS diagnosis, that's evidence that failure of axon transport is a key issue in ALS. Many theories have been proposed regarding axon transport deficiencies in ALS, but perhaps the simplest theory is that aggregates clog the machine.

Then there's bulbar. Direct connection between brain and muscle, no spinal ganglion. And we aren't talking a meter long axon, several centimeters will suffice. There is a neuromuscular junction.

Bulbar onset seems to manifest two populations, fast progressors and slow progressors. Bulbar by itself seems to be rare and would not be classified as ALS. Fast progression with bulbar onset would therefore seem to be a disease of the neuromuscular junction.

Bulbar onset with slow progression seems to be associated with primarily UMN symptoms. In other words, whatever it is, it's not primarily a disease of the neuromuscular junction, and it's not primarily a disease of the spinal ganglia either although it may eventually get there (and beyond to the lower motor neurons).


One of the hardest parts of advocacy for support of ALS research and of ALS patients and caregivers, is in communicating its relevance to people who have no experience with it.

If you don't already have ALS, your chance of developing ALS is about 1 in 800. That's not big, but it's not insignificant either. There are lots of life-changing diseases with incidence about the same or lower, but they get more attention because the people who get those diseases are not so thoroughly taken out of the public eye so quickly. 

I have often criticized ALS advocacy efforts that were based on "Million Man March on Washington" or "AIDS Drug Armtwisting" models. That's where the 3.9/100,000 prevalence data tells the truth. Of those 3.9, something close to 100% are so preoccupied with issues of daily survival that there is nothing left for advocacy. 

Want a number? Here's one. Let's say that of those (call it 4/100,000 round numbers), we have on the average 2 1/2% left over for advocacy. The overwhelming majority of us have nothing for advocacy, but a very few have quite a bit. Call it 2 1/2 %. Reality check: it's probably more than 1% and it's not likely more than 5%. Nobody can prove that 2 1/2% is the best number, but it passes the "reality check" test. 

It's grade school math time again. That's 300 ALS advocate poster children in the entire USA. And, we're not the cutest Jerry's Kids in the MDA club, no wonder they divorced us! 

The actual history of ALS advocacy is a reality check on that 300 number. Three hundred almost never happens. 

So, please, let's scrap that civil rights march way of thinking! We're not a minority, we're one in 25,000 people, and of those we're mostly unavailable for any struggle but our own personal struggle. We're really crappy at marching. 

The key to getting public attention is not our numbers, it's their numbers. 

Their number is 1 in 800. 

Let's put that into context. In the USA, your risk of dying from homicide is about 1 in 200. When it comes to homicide, we have whole genres of television and literature devoted to the subject, we have huge industries devoted to preventing it, we have a huge publicity machine telling stories about every day, and we spend huge amounts of money on prosecuting murder cases and then throwing the perps into prison. We never have to explain to anyone what murder is, even grade school kids know. 

We're almost in that same league, and we're invisible. Our invisibility isn't likely to change very much any time soon. Ten thousand wheelchairs in front of the White House wouldn't change a thing, and a mere 100 are not likely available. 

The key to making it important to folks who don't have it, is not prevalence. It's incidence. Whatever the nation spends on preventing causes of death, ALS deserves about 1/800 of it. I don't have numbers handy, but I really doubt anything like that is being spent to prevent death by ALS.