William K. Reid, M.D.Hematology & Oncology 613 Greenwood Rd.
Chapel Hill, N.C. 27514 Cellular: (615)405-5162 Email:
wkrmd2017@gmail.com
Monday, January 25, 2021
Hypothesis: Mycotoxins Causing Amyotrophic Lateral
Sclerosis
Reviewer’s questions:
1. Pattern of Cascade through the Neuroaxis in ALS
2. Biomarkers for ALS & for Mycotoxins
I. ALS Cascade Upper & Lower Motor Neurons :
It is intriguing to relate the available data on neurotoxic mycotoxins
with the clinical findings in ALS. ALS is a motor neuron disease with
insidious, progressive weakness and muscle wasting. One of the essential
clues to the diagnosis of ALS is the involvement of both upper and lower
motor neuron disease. The diagnostic strategy presented by Statland et
al 20151 defines upper motor neuron deficits with
spasticity and hyperreflexia and lower motor neuron disease with muscle
wasting, weakness, fasciculations, fibrillations and positive sharp
waves. In ALS there is a mixture of both upper and lower motor neuron
deficits. The pathology of the neurotoxic mycotoxins, especially the
trichothecenes(Dai, C. et al 20192), closely mimics
the pathology of ALS with oxidative stress, mitochondrial dysfunction
and respiratory chain damage.
Intranasal Pathways Bypass of Blood Brain Barrier & CSF :
The trichothecenes, T-2 Toxin and Deoxynivalenol, are major contaminants
of the world food supply. If the opportunistic fungi responsible for
these secondary metabolites develop a niche in the body by colonization
or infection, these potent, lipophilic mycotoxins are able to cross
barriers, especially the blood brain barrier and accumulate in the brain
and spinal cord. Marcesca, M. 20133 reports on of
transport of food-associated trichothecenes from the gut to the brain.
There is a more intriguing possibility if there is a focus of a fungal
infection in the upper airway, especially the upper sinus cavity. There
is a growing body of research documenting intranasal delivery of
compounds and drugs to the brain and spinal cord. Thorne, R.G. et al
2004 4report on transport of IGF-1 in the nose of
rats. Thorne, R.G. et al 20085 report on transfer of
interferon-beta in a monkey’s nose to brain. There are extensive studies
documenting intranasal absorption of insulin in the objective of
replacing injection requirements. Lochhead, J.J. et al
20196 found insulin had neuroprotective effects
traveling along the trigeminal nerve. Avgerinos, K.L. et al
20187 found intranasal insulin in 293 patients
improved memory in patients with Alzheimer’s or mild cognitive deficits.
Intranasal glucagon was effective in adults with type 1 diabetes and
insulin-induced hypoglycemia (Rickels, M.R. et al
20168). What these studies discovered are pathways
bypassing the blood brain barrier as well as the CSF.
Pardridge, W.M. in 20119 and 201210UCLA pointed out misconceptions surrounding drug and compound levels in
the CSF, blood and brain. His studies showed that CSF drug levels were
the same as systemic blood levels and were not equivalent to brain or
spinal cord levels. Over the past 10 years the literature has defined
two intranasal pathways that bypass both the CSF and the blood brain
barrier.
The upper sinus cavity is lined by olfactory mucosa that has direct
passage of olfactory nerve endings exposed to the external environment.
There is a second lining of respiratory mucosa fed by the ophthalmic and
maxillary branches trigeminal nerve. Djupesland, P.G. et al
201411 describes the delivery of drugs from the nasal
cavity directly into the brain. Passage is rapid in 5 minutes to 60
minutes passing by convective or bulk flow. Drugs bypass the blood brain
barrier and the CSF.
The olfactory pathway passes compounds of significant size into the
olfactory bulb. The drugs move outside of the neurons with movement by
pulsatile flow extracellular pathways. The trigeminal pathways from
nasal cavity to brain moves to the midbrain, pons and the lower motor
neurons of the spinal cord. The olfactory pathway feeds into the limbic
system and forebrain.
If there is an infection of the upper nasal cavity involving
opportunistic fungi, such as Fusarium species that release lipophilic,
neurotoxic mycotoxins, it could poison the brain and spinal cord in an
insidious fashion. The pathway from the olfactory bulb to the upper
brain would involve the upper motor neurons. The pathway from the
trigeminal nerve branches would transport drugs to the brainstem and
lower motor neurons (Djupesland, P.G. et al 201411,
Lochhead, J.J. et al 201512, Ganger, S. &
Schindowski, J. 201813). There are studies of giving
chemotherapy intranasally for glioblastoma multiforme (Bruinsmann, F.A.
et al 201914, van Woensel, M. et al
201315).
Pseudobulbar Affect :
Intranasal passage of neurotoxins into the brain and spinal cord would
explain the dual injury to upper and lower motor neurons. The olfactory
intranasal pathway leads to the olfactory bulb and limbic system. This
pathway could help to explain pseudobulbar affect. Thakore, N.J. &
Pioro, E.P. 201716 in Cleveland reported on
pseudobulbar affect found in 209 out of 735 ALS patients. They found an
association with bulbar onset and dysfunction with predominantly upper
motor neuron disease. The ALS patients with pseudobulbar affect were
younger in age with a shorter duration of disease. They found an
association with worse bulbar findings, dysarthria and dysphagia. There
was an association with the use of Baclofen, a surrogate for upper motor
neuron dysfunction.
Misconceptions of Blood Brain Barrier & CSF :
Pardridge 20119 and 201210, report
on the literature before 2011 with the misconceptions about CSF drug and
metabolite levels. The intranasal passage of drugs and metabolites to
the brain did not feed into the CSF. This leads to misconceptions when
studies assume CSF levels are equivalent to brain and spinal cord
levels. In order to get accurate brain levels requires Intracerebral
Microdialysis, PET scans or functional MRI (Chefer, V.I. et al
200917, Lasley, S.M. 201918).