The Ependyma As A Major Player in the Pathogenesis of Amyotrophic Lateral Sclerosis: A Hypothesis
Anthony G. Payne, Ph.D.
Amyotrophic lateral sclerosis (ALS) is an insidious, mercilessly devastating disorder in which motor neurons that control voluntary movement are progressively lost while those that are involved in cognition and sensation are spared. At this time ALS sufferers have no scientifically validated treatment options available to them. Fifty percent succumb within three years of symptom onset and between eighty and ninety percent within five years.
At this point-in-time ALS has a complex, incompletely understood etiology. Approximately 5- 10% of cases have a genetic basis (familial ALS or fALS), with the remainder having no clearly discernible cause. The best that can be said is that ALS is very likely a multifactorial disorder triggered by any number of exposures such as environmental toxicants, either alone or in combination with specific genetic factors). This is underscored by the fact that an approximately two-fold increase in the risk of developing ALS appeared among military personnel deployed to Southwest Asia during the Gulf War (Aug 1990-July 1991) compared to non-deployed personnel.
Once the ALS disease process is underway, there are a number of pathogenic mechanisms that are felt to bring about the cellular dysfunction and apoptosis in motor neurons that are characteristic of the disease:
(1) Mitochondrial dysfunction involving, in part, oxidative stress.
(2) Excitotoxicity due, in part, to a down regulation of motor neuron glutamate transporters.
(3) A loss of calcium homeostasis in motor neurons.
(4) Disrupted protein synthesis and processing.
(5) Altered neuronal cytoskeletal function and axonal transport.
(6) Dysfunction of astrocytes and glial cells that support the CNS in general, as well as motot neurons.
Current therapeutic intervention is aimed at modulating the various pathogenic processes. Research is ongoing and involves such things as use of intravenous (IV) Ceftriaxone to upregulate glutamate transporter genes and protein expression in motor neurons.
It is proposed by the author that at least some cases of ALS arise due to defective specialized neuroglial cells called ependymal cells, especially modified ependymal cells called choroidal cells that are involved in the synthesis and circulation of cerebrospinal fluid and maintenance of the blood-CSF barrier. These cells may arise, at least in part, as the end result of deleterious mutations or possibly epigenetic influences. As a result of these cellular defects in the choroidal cells, cerebrospinal fluid is synthesized that is laden with compounds that are neurotoxic, especially with respect to motor neurons, as well as rich in inflammatory cytokines and such. It is the circulation of this aberrant CSF that brings some (and in some instances perhaps all) of the pathogenic features that characterize some cases of ALS.
Support for this hypothesis comes from two sources:
(1) Direct: Published studies that show that CSF taken from ALS patients induces neurodegeneration characteristic of ALS in lab animals.
(2) Indirect: Seeming retardation in disease progression in four (4) ALS patients who have been following a regimen that modulates neurodegenerative processes shown to result when CSF from ALS patients is administered to lab animals and used in cell cultures.
Hypothesis Support - Studies
A. In a lab study conducted in India , motor neurons and spinal cord neurons in culture were exposed to CSF from 20 ALS patients and 20 controls. The “Exposure of cells to ALS-CSF drastically decreased the survival rate of motor neurons to 32.26+/-2.06% whereas a moderate decrease was observed in case of other spinal neurons (67.90+/-2.04%). In cultures treated with disease control CSF, a small decrease was observed in the survival rate with 80.14+/-2.00% and 90.07+/-1.37% survival of motor neuron and other spinal neurons respectively.” The die-off of spinal cord cells exposed to CSF from ALS patients was linked to elevation of intracellular calcium, while that of motor neurons to “activation of glutamate receptors, the AMPA/kainate receptor playing the major role.”Sen I, Nalini A, Joshi NB, Joshi PG.
B. “CSF was injected intrathecally into three-day-old rat pups and subsequently the ultrastructural changes in the motor neurons were studied after 48 h, 1, 2 and 3 weeks. We observed that ALS-CSF causes fragmentation of the Golgi apparatus in a considerable number of motor neurons in the spinal cord. This was further confirmed when motor neurons were stained with an antibody against a medial Golgi protein (MG160). Thus, we suggest that the putative toxin(s) present in ALS-CSF may cause impairment in the protein processing leading to motor neuron death. “ Ramamohan PY, Gourie-Devi M, Nalini A, Shobha K, Ramamohan Y, Joshi P, Raju TR.
C. “... earlier studies have shown that cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients causes death of motor neurons, both in in-vitro as well as in-vivo. There was an aberrant phosphorylation of neurofilaments in cultured spinal cord neurons of chick and rats following exposure to CSF of ALS patients (ALS-CSF). Other features of neurodegeneration, such as swollen neuronal soma and beading of neurites were also observed. In neonatal rat pups exposed to ALS-CSF, we observed phosphorylated neurofilaments in the soma of spinal motor neurons in addition to the increased lactate dehydrogenase activity and reactive astrogliosis. The present study examines the effect of ALS-CSF on the expression of glial glutamate transporter (GLT-1) in embryonic rat spinal cord cultures as well as in spinal astrocytes of neonatal rats. Immunostaining suggested a decrease in the expression of GLT-1 by astrocytes both in culture and in-vivo following exposure to ALS-CSF. Our results provide evidence that toxic factor(s) present in ALS-CSF depletes GLT-1 expression. This could lead to an increased level of glutamate in the synaptic pool causing excitotoxicity to motor neurons, possibly by triggering the 'glutamate-mediated toxicity-pathway'. Shobha K, Vijayalakshmi K, Alladi PA, Nalini A, Sathyaprabha TN, Raju TR.
D. “In the present study we show that there is an increased number of astrocytes intensely immunoreactive for glial fibrillary acidic protein (GFAP) in the gray matter of the spinal cords of neonatal rats exposed to ALS CSF. There is also increased expression of GFAP in the astrocytes of the white matter of neonatal rat spinal cords exposed to ALS CSF. Western blot analysis also confirmed the increased expression of GFAP. Accordingly, our study provides for the first time a clear evidence for the pathological response of glia to the circulating toxic factor(s) in the CSF of ALS patients.” Shahani N, Nalini A, Gourie-Devi M, Raju TR.
There are other studies, most cell culture or animal, which directly or indirectly indicate that the CSF of ALS patients contains compounds that are neurotoxic, inflammatory and proinflammatory, and otherwise contributory to pathogenic mechanisms common to ALS.
The impact of these CSF compounds can be summarized briefly as follows:
(1) Intracellular calcium is elevated in spinal cord neurons.
(2) Glutamate levels rise and receptors are activated in motor neurons.
(3) Some appear to lower quinine reductase levels in motor neurons and possibly astrocytes, which results in increased glutamate influx.
(4) Mitochondrial dysfunction occurs and with this compromised motor neuron energetics.
(5) Neuroinflammation increases.
(6) Antioxidant defenses such as glutathione are increasingly at risk of depletion or depleted.
Some of these effects overlap those of other players, both genetic and non-genetic, in ALS. As such, it is likely that therapeutic intervention with respect to modulating synthesis of neurotoxic, etc. compounds in the CSF or their impact on spinal cord and motor neurons, moderates the impact of these other players.
This aside, it follows that if some or most nonfamilial ALS patients owe at least part of their condition to damage wrought by various neurotoxic, inflammatory and proinflammatory, etc. compounds in their CSF, dietary, pharmacologic and nutraceutical measures that lower or otherwise modulate the synthesis of these substances or attenuate their impact on motor neurons will slow disease progression and prolong lifespan.
With this in mind, the author tooled together just such a regimen (2005 with subsequent modifications) consisting of:
CoQ10 (Ubiquinone/ubiquinol): Rationale for use – CoQ10 appears compromised in ALS. Dose: 200 mgs. every 2 hours during the day (1200 mgs daily)
Noni juice or capsules – Rationale for use: Contains a potent quinone reductase inducer – QR reduces glutamate toxicity in cells. Dosage: Juice to be drunk liberally all day long. Capsules – 1 every 2 hours during the day and 1-2 capsules one hour to one-half hour before bedtime.
Tumeric Extract Tablets or Capsules – Rationale for use: Quinone reductase inducer in astrocytes (Lowers glutamate). Dose: 1 (.05 gram) tablet every two hours during the day and 1-2 tablets prior to bedtime.
DEPRENYL: According to a 1994 animal study, “CSF samples from ALS and non-ALS neurological patients were injected into the spinal subarachnoid space of 3-day-old rat pups, followed by a single dose (0.01 mg/kg body weight) of (-)-deprenyl, administered 24 h after CSF injection. After a further period of 24 h, the rats were sacrificed and the spinal cord sections were stained with antibodies against phosphorylated neurofilament (NF, SMI-31 antibody) and glial fibrillary acidic protein (GFAP). Activity of lactate dehydrogenase (LDH) was also measured. (-)-Deprenyl injection resulted in a significant (61%) decrease in the number of SMI-31 stained neuronal soma in the ventral horn of the spinal cord of ALS CSF exposed rats. This was accompanied by a reduction in the astrocytes immunoreactive for GFAP. There was also a significant (35%) decrease in the LDH activity following (-)-deprenyl treatment. These results suggest that (-)-deprenyl may confer neuroprotection against the toxic factor(s) present in ALS CSF.” Shahani N, Gourie-Devi M, Nalini A, Rammohan P, Shobha K, Harsha HN, Raju TR.
Dose: Discretionary with each patient’s physician. Use of patches or oral forms (Pills, tablets or liquid). The typical daily dose was 12 mgs/daily.
IV Glutathione: Rationale – depleted in many ALS patients or at risk of becoming so. The intravenous (IV) dose is determined by each patient’s physician. During 2007 a patented oral form of glutathione became available, one that is absorbed through the oral mucosa and resists breakdown until it reaches the CNS (Th-Queen from Italy ).
PREVAGEN (Aequorin) – Rationale for use: Prevents calcium influx and resultant toxicity in neurons. Dose: One twenty milligram (20 mg) capsules every 2 to 3 hours during waking hours and one to two (1-2) capsules 30-60 minutes before retiring for the night. Aequorin became available commercially during 2007 and was added to the regimen at that time.
Lithium – Rational for use: Glutamate modulation in neurons. Dose: 250 mgs. to 600 mgs Lithium carbonate daily (Dosage determined by each patient’s neurologist or primary care physician). Lithium was added to the regimen during 2007.
Diet: Medium Chain Triglycerides Diet. Rationale: There are many reasons the ketogenic or MCT diets might be of benefit to ALS patients, not the least of which is the fact they tend to increase glutamate transporter gene expression.
Ketogenic & MCT Diet (Epilepsy website)
Hypothesis Support – Clinical Responses (n=4)
Four individuals diagnosed with nonfamilial ALS (3 male, 1 female, ages 35-52) adopted the regimen outlined above beginning during 2005, all with their primary care physician or neurologist’s participation (Note that Prevagen was introduced during 2007 when it became available. Lithium was likewise added during 2007). All four experienced disease progression, however when compared to age- and disease matched controls, the degree of progression is decidedly less. One (male) patient noted that “Every single ALS patient diagnosed at the same time I was (diagnosed) is now dead or on a respirator. I am still walking, talking, eating and living my life. I’ve lost some functioning in my hands and arms, but this is not so great as to rob me of doing things I need to do like driving my car”.
While the responses of these six is far from definitive and cannot be called rigorous in the scientific sense, it is suggestive and offers a very tentative confirmation of the hypothesis put forward.
A greater degree of confirmation will come when, for example, the choroidal cells in the brains of ALS are replaced in whole or part by healthy counterparts produced from stem cells. In accordance with this hypothesis, it is expected that synthesis and circulation of a healthy CSF will result in a significant degree of disease progression or even disease arrest.
See also this variation of the regimen cited in this paper: Retarding ALS Progression
© 2008 by Dr. Anthony G. Payne. All rights reserved. The information contained in this article is provided for informational purposes only and should not be construed as medical advice or instruction. Readers are advised to consult a licensed health care professional concerning all matters related to their health and well being.