Intranasal Pathways Bypass the Blood Brain Barrier and the CSF
There is an intriguing possibility to explain the findings in ALS. If
there is a focus of a fungal infection in the upper airway, especially
the upper sinus cavity, the release of neurotoxic mycotoxins would
rapidly move into both upper brain and lower spinal cord. There is a
growing body of research documenting intranasal delivery of compounds
and drugs into the brain and spinal cord. Thorne, R.G. et al
200431 report on transport of IGF-1 to the brain from
the nose of rats. Thorne, R.G. et al 200832 report on
the transfer of interferon-beta from the nose to the brain of monkeys.
There is extensive research on intranasal absorption of insulin with the
objective of replacing injection requirements. These studies found
intranasal insulin was a viable route of delivery to the systemic blood
stream. It also discovered that insulin was passing directly into the
brain and spinal cord. Lochhead, J.J. et al 201933found insulin had neuroprotective effects given intranasally. It
traveled along branches of the trigeminal nerve. Avgerinos, K.L. et al
201834 found that intranasal insulin in 293 patients
improved memory in patients with Alzheimer’s or mild cognitive deficits.
Rickels, M.R. et al 201635 found that intranasal
glucagon was effective in adults with type 1 diabetes mellitus in
insulin induced hypoglycemia.
Studies by Pardridge et al 201136 and Pardridge et al
201237 document the passage of compounds by bulk flow
along the course of the olfactory nerve to the olfactory bulb. Compounds
enter into the brain at the level of the limbic system and forebrain.
This would give rapid access to upper motor neurons. A second course
from the sinus cavity follows two branches of the trigeminal nerve,
ophthalmic and maxillary branches moving into the midbrain and spinal
cord giving rapid access to lower motor neurons. Insulin 5.8 kDa gains
access to the CNS within 5-30 minutes.
Pseudobulbar Affect :
The rapid access to the limbic system and forebrain via the olfactory
nerve pathway could help to explain pseudobulbar affect. Thakore, N.J.
& Pioro, E.P. 201738 in Cleveland reported on
pseudobulbar affect disorder found in 209 out of 735 ALS patients. They found
an association of bulbar onset and dysfunction with
predominant upper motor neuron disease. The ALS patients with
pseudobulbar affect were younger in age with a shorter duration of
disease. There was an association with the use of Baclofen, a surrogate
for upper motor neuron dysfunction.
Misconceptions of the Blood Brain Barrier and CSF :
Pardridge et al 201237 pointed out the misconceptions
in the literature related to drugs and compound levels in the CSF.
There was the misconception that CSF drug levels equated to levels in
the brain and spinal cord. They found that CSF drug and compound levels
were equivolent to systemic blood levels and not brain tissue levels. To
assess brain and spinal cord drug levels required intracerebral
microdialysis, functional MRI or PET scan.
Biomarkers for ALS :
The biomarkers listed for ALS are documented in many articles including
Vu, L.T. & Bowser, R. 201739. Comparing these
biomarkers for ALS with those found with mycotoxins finds similarities
in multiple categories. Both lists include biomarkers for mitochondrial
dysfunction and for immunologic deficits. An article by Vidal, A. et al
201840 reviews the use of GC/mass spectroscopy to
screen the world food supply for mycotoxins.