an ALS Hypothesis - extended to all 'abnormal' neural atrophy

kenneth Collins kpaulc at
Wed Feb 2 20:55:31 EST 2000

hi, John.

John H. wrote:
> <dag.stenberg at> wrote in message
> news:8766kn$bad$1 at
> > kenneth Collins <kpaulc at> wrote:
> > > i've reformatted my prior post to make online reading easier.
> >
> > Ah, now it is all right.
> >
> > Most points in your previous message are now clearly explained.
> > I think that (descrambled) hypothesis is quite worth to read. It may be
> > way off road, but at least the details and reasoning deserve thinking
> > about.
> >
> > > the main thing that stimmed this 'dietary' stuff was with respect to the
> > > problem represented by the 'late onset' of the disease conditions, which
> > > needs explication. if, in accord with the traditional view, it actually
> > > is the case that a single DNA mutation results it the entirety of the
> > > disease condition(s), then why is it that the stuff of that mutation is
> > > activated in such a delayed way?
> Cancer.

yes, =anything= that 're-engineers' the neural topology can generate the
sort of 'lesion' that i've been focussing upon in my discussion.

> > For comparison: in prion diseases, it takes times for anomalous PrP to
> > develop and for deposits to accumulate.
> >
> > > >> i relied on the discussion of ALS in Kandel, et. al. for my
> > > >> start. the factors that i found significant are as follows.
> >
> > > >> the Hypothesis:
> >
> > I had not earlier been able to find this among the over-long lines.
> >
> > > >> the demyelination results from a specific brain stem lesion,
> > > >> of a type analogous to the chemically-induced vestibular
> > > >> lesion, or a stroke-induced lesion.
> > > >> ...
> >
> > I do not see any explanation for the fact that brain stem symptoms are
> > usually later in appearance than limb involvement. It also seems to
> > neglect observable peripheral pathology.
> >
> > > >> there are other attractive rationales for this sort of
> > > >> hypothesis. the problem of the 35+ years typical onset of
> > > >> ALS has to be explained. if there's a genetic flaw, then how
> > > >> is it that it shows itself only after 35+ years? what's the
> > > >> 'switch' that changes fully-functional motor neurons to
> > > >> dysfunctional 'motor' neurons?
> >
> > Interesting question, no doubt.
> Remember Huntingtons, 45 copies or repeats and away it goes, but that takes
> until middle age, although non symptomatic pathology is present for quite a
> while. I don't see these things as turn on\turn off objects. There is a
> battle going on here but time gives pathology the inevitable edge. The
> question of late onset does not concern me too much. I suppose my view is
> that the brain begins with a head start (literally) but time eventually
> takes its toll. Live long enough and we'll all be fascinated by Teletubbies.

i agree with your last statement, but am 'looking-eleswhere' with
express respect to premature versions of such.

> >
> > > if this sort of thing occurs, then the disease is treatable through
> > > methods that eliminate the functionality of the newly-triggered stuff,
> > How would you diagnose the disease 35+ years before outbreak?
> > > at any rate, an explanation for the observed delayed onsets of
> > > Alzheimer's, ALS and Huntington's is necessary, and it will probably be
> > > the case that, when such delayed onset is explained, treatment
> > > strategies will become apparent within such explanation. so explication
> > > of the delayed onset is an important problem.
> >
> > > >> the one criterion that =must= be met in order to explore
> > > >> this hypothesis further is, since the ocular motor system is
> > > >> not affected in ALS, to culture examples of ocular motor
> > > >> neurons  along with examples of upper and lower motor
> > > >> neurons, and look for differences that would allow the
> > > >> ocular motor neurons to survive while the upper/lower motor
> > > >> neurons would not survive.
> >
> > This seems to me a profitable approach. Objections, anyone?
> Thanks Ken, I wasn't aware of this. Another item for the database. Can you
> ref?

the 'sparing' of ocular motor function is in the basic (textbook)
literature that i cited earlier in the thread. as far as the call to
culture and compare ocular motor neurons and upper and lower motor
neurons, that just became ovbious to me as i read.

> The differences you may need to find could take forever.

make a 'slurry' and use generalized differential 'gel-mobility'
technigues to get a start. since the neurons would be cultured, their
intrinsic variation could be minimized.

> Interesting idea
> though. Practically I have no idea if the two cell types can be in suitably
> similiar cultures and even if possible the setup may mitigate the benefits.

i'm just calling for gross factors, which correlate to the fact that
upper- lower-motor neurons undergo degeneration, while ocular motor
neurons do not.

and exploration into such is 'just' one means to test the hypothesis
i've been discussing... that it's a 'lesion'-induced 'co-opting' of the
cerebellum's =normal= TD E/I-minimization functionality that
precipitates the 'disease' observables.

> The problem may lie outside the cells. Transporters?

if it was one of the major transmitters, that would've been realized by
now. i did include the possibility that it's a 'minor' (peptidergic?)
transmitter problem that results in the hypothetical 'lesion' dynamics
that i've been discussing. that's why i spent so much 'time' emphasizing
dietary and external chemo, etc. stuff.

it could be as you say, John.

whoops! you said 'transporters', but i read 'transmitters'. i'll leave
my discussion.

in my reading, the thing that mitigates against discrete 'molecular'
failure is that the pathology is so-readily seen to occur as a function
of normally-integrated neural dynamics.

if there was a discrete 'molecular' failure, it would seem that it would
'break the chain' of all this normally-integrated functionality in a way
that'd be readily-apparent.

but, instead, the normal chain remains unbroken, but, obviously, being
driven in an aberrant fashion.

my approach focusses upon discovering what it is that drives the
normally-integrated chain of neural dynamics, aberrantly, and how 'it'
does so.

but the normal chain of neural dynamics is still, obviously, in-there.

> It may not be anything
> specific deficit, a subtle allele that tips the balance, this or that
> doesn't work so well over time and it's just going downhill faster.

yes, but not, in my hypothesis, i account, fully (=hypothetically=), for
why things are 'running-downhill'.

> The brain is a chaos fighter,

yes, the brain does TD E/I-minimization.

> but some brains just can't win against some chaos.

i've a lot of personal experience with respect to such :-)

sereiously, though, in the present matter, it's obvious that there's an
integrated, coordinated, 'going downhill' that's
exquisitely-well-correlated to the cerebellum's =normal= integrated
functionality, and which can =certainly= be generated via the 'lesion'
dynamics that are described in the hypothesis i've been discussing.

the cerebellum is 'just' functioning normally, in the 'face' of
aberrant, non-minimizable TD E/I(up). because it can't eliminate the
'lesion'-interjected TD E/I(up), the cerebellum's normal TD
E/I-minimization dynamics 'shut down' =normal= stuff, as a result of
it's =normal= TD E/I-minimizing function.

one can leiterally see all of this in descriptions of the degeneration's

> I can't see any switches, I'm running with James Clerk Maxwell on this one,
> "The laws of probability is the true logic of nature."

let's see, you're talking about a 'switch' with respect to late-onset.

other than the hypothetical "lesion's" establishment, i've only
discussed chemical & dietary, etc., stuff that needs to be explored.

in this view, there might be a genetic suseptibility that is triggered
by a 'chemo' factor, and the dynamics that are precipitated could be
prevented by getting a handle on such stuff, allowing suseptible folks
to steer-clear of that stuff, and, thus, avoid triggering the 'disease'

> Need to know exactly where the ocular muscles receive innervation. Eg. v.
> close to eyeball, on or very close to its surface.

the ocular motor nerves have extensive involvements up and down the
entire neuraxis. that is, inputs deriving in many, widely-distributed
areas activate them.

that's why i included the superior colliculus in the example i included
in the first statement of the hypothesis. the idea was that ocular motor
functionality, including its cerebellar correlates, remains normal, but
the normal routing of activation pertaining to visual saccadic movement,
which is inherently relatively-random (thereby constituting the
necessary non-minimizable TD E/I(up)) is 're-engineered' before it's
projected to the cerebellum. i invoked the inferior olive because it's
easy to account for such 'getting-mixed-up' stuff within the inferior
olive's 'translation' dynamics (which, BTW, as far as i know are still
only explicated in NDT (see AoK, Ap6)), and, from inferior olive, being
passed on, aberrancy already established, via the potent climbing-fiber
projections of the inferior olive to the cerebellum.

and, because of the cerebellum's globally-integrated TD E/I-minimization
dynamics, that's all it would take to generate the =complete=
degeneration 'picture'.

the cerebellum cannot eliminate the saccadically-correlated activation
that's been miss-mapped by the hypothetical lesion, and is 'confused'
with respect to it, reacting to it as if it's coming from normal motor
areas. so the cerebellum progects TD E/I-minimization back to those
motor areas. but since the TD E/I that the cerebellum is 'attempting' to
minimize is correlated, on the input 'side', with 'lesion' miss-mapped
saccadic activation, the TD E/I-minimizinf force that the cerebellum
projects back to the motor areas shuts down =normal= motor activation.

and since the 'lesion'-interjected TD E/I(up) activation can't be TD
E/I-minimized, the cerebellum's TD E/I-minimization dynamics gradually
shut down more and more =normal= motor stuff.

this can account for all the observed atrophy.

(but, note well, even though it's gaining increased 'sustenance' the
more i explore it, it's all 'just' an hypothesis that needs

> Perhaps the ocular
> nerves, being that close to the CNS, receive a relatively rich supply of NGF
> or acetycholine, thus prolonging their life. Perhaps very late in ALS there
> is motor ocular pathology.  (help with neuroanatomy!)

i've not come across any accounts of ocular motor deficits, although, in
'dementia', ocular motor dynamics must reflect that 'state'. (but my
reading with respect to the disease conditions must still be considered

> Vaguely, remember reading something about eyes being "immune privileged".

that'd be significant.

> Not sure what that means and know it refers to inside the eyeball, but I do
> wonder if it may be relevant.
> > > i repeat, i'm taking this position in this hypothesis because all of the
> > > so-called 'indicators' that i've read of can result from excitotoxic
> > > activation, which means that it's possible that the 'indicators' are
> > > nothing of the kind, but 'only' by-products of a
> > > more-globally-correlated set of dynamics, such as those that i've been
> > > discussing in this hypothesis.
> I'm not sure that AD is a result of excitotoxic activation. I am much more
> inclined to think of each pathology specifically, from what I've seen lately
> the exact opposite can also initiate cell death: excito nothing. Nerves
> cells need innervation. The middle way?

i was addressing the mitochondrial vacuoles, etc. also have come across
a ref that discusses 'swollen' schwan cells, which fits with an 'excito
toxic' view.

but, in the hypothesis i've been discussing, the 'excito toxic'
conditions are not the 'disease'. they are the result of the aberrant TD
E/I-minimization dynamics that i've been discussing. the result of the
cerebellum's projecting back activation that prevents the achievement of
type II synchronization in the upper and lower motor neurons, which, as
i've discussed in previous msgs, would force the schwan cells to be
constantly 'adjusting', and since such 'adjusting' cannot be successful,
because of the abberant activation dynamics occurring at higher
'levels', the schwan cells become 'over-taxed', and die, which
constitutes a progression that feeds-back, causing the TD E/I(up)
dynamics at higer 'levels' to become exacerbated.

of all of this last stuff, what's significant is that the microscopic
neuronal observables are all accounted for in a way that sees that the
neurons and schwan cells have been overly 'stressed', which is different
from the view that seeks to account for the pathology via a
intra-cellular 'molecular' dysfunction.

anyway, Thank You for presenting the opportunity for further discussion
(which 'need', if anyone 'wonders') is a correlate of my 'propensity' to
Guard Free Will.)

ken (k. p. collins)

> John.
> > Logical. Not necessarily true, but logical.
> >
> > > anyway, that's my contribution(?) to the efforts to extinguish these
> > > diseases. i could do more, but despite the fact that i've done this
> > > stuff at my own expense, i've only been 'ridiculed' for having tried
> >
> > I think this (descrambled) hypothesis is quite worth to read. It may be
> > way off road, but at least the details and reasoning deserve thinking
> > about.
> >
> > Dag Stenberg

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