Histopathology as an Approach to Schizophrenia

Alzheimer reported focal destruction of neurons in the gray matter and cytoarchitectonic disturbances in 1900. Alzheimer, who was later confirmed by Josephy, regarded these changes as characteristic of "dementia praecox". In 1923 H. Josephy reported pathology in "dementia praecox". In 1937 Funfgeld also reported pathology in the same disease.

Findings

Various researchers have reported pathologic alterations in the structure of neurons. These have included sclerosis, the disappearance of the tigroid bodies (the synthetic apparatus of the cell), pyknosis of the nuclei, and accumulations of lipoids. This author (Olson) has formed a massive theory which explains most of these findings. I figured out that the destruction of the tigroid bodies, which are filled with amino acids, was caused by an excess of amino acids in the cells. The fat is explained because the cells are overeating amino acids. The nucleus is affected because RNA is used up in the process of making proteins. Since this process is going haywire, there is an excessive demand for RNA by the cell. The case of fatal catatonia is an interesting one. In fatal catatonia the patient dies from the "mental" disease. They go into a catatonic stupor and sometimes die. Alzheimer examined this in 1913. This was not Alzheimer's disease, which he had reported earlier. However, death can occur in Alzheimer's disease. In 1909 Sioli examined catatonia. Alzheimer, Sioli, and Fankhauser all reported ameboid degeneration of the astroglia. This directly contradicts neurodevelopmental theories since neurodevelopmental disease are not associated with gliosis.

In 1952 Scharenberg and Brown of Michigan studied catatonia with silver carbonate. They found swollen neurons. They also found destruction of intracellular structures. This further supports the amino acid theory. If amino acids were flooding the brain, the neurons would swell up and certain structures which contain amino acids would undergo destruction These structures would be the tigroid substance and the mitochondria.

All of this supports orthomolecular psychiatry. A diet very low in amino acids is suggested as a possible treatment.

The Neuropathology of Schizophrenia

A number of workers have researched this area, including Professor V. A. Romasenko of Moscow. Another Moscow worker was L. I. Sukhoukova, who published a brilliant report in 1969. Sukhorukova, a big name in Soviet neuropathology, used the electron microscope to study "the ultrastructure of the cerebral cortex" in schizophrenia and epilepsy. He used "bioptic" material, which is called "biopsy" material in American publications.

Sukhorukova Results

One patient was 21 years old. She had made several suicide attempts. She complained of headaches and insomnia. A leukotomy was performed. This was done in Budapest. Brain tissues were removed from the upper layers of the frontal cortex (the superior frontal gyrus). These tissues were studied under the electron microscope. "A pronounced enlargement in the diameter of cisternae and an increase in their number in the granular endoplasmic reticulum" were seen. Also "an accumulation of lipofuscin-like granules in the cytoplasm of neurons and glial elements were prominent on the electron photomicrographs". Abnormalities were also seen in the nucleus. "The profiles of membranes delimiting vacuoles of enlarged cisternae in the endoplasmic reticulum were often indistinct, with obliterated outlines." In the mitochondria there was "swelling and central lysis of cristae". Astroglial cells contained "a considerable quantity of dark glycogen-like granules of varying sizes". If these granules are glycogen, this might signify a partial failure of glucose metabolism. Astrocyte processes around neurons and vessels "appeared considerably enlarged and osmiophobic". This could signify that the astrocytes are overeating something. The fact that there was pathology to the cell membranes could signify a toxic factor attacking the membranes. It could also mean that the cell is swelling up like a balloon, which would distend the membrane. If the cell swells up to much it would burst, as is seen in hemolysis. Both explanations could be true.

The meaning of the "lipofuscin-like granules" is not clear. They could represent neuromelanin, or perhaps an abnormal form of neuromelanin. Neuromelanin comes from dopamine. This appears to suggest an excess of some dopamine metabolite, perhaps an abnormal one. The "vauoloid inclusions" could represent fat, which is sometimes found in vacuoles. Again this suggests that the cell may be overeating something. The fact that "cisternae of the endoplasmic reticulum were dilated" suggests amino acids. Amino acids are stored in these cisternae in order to build proteins from them. Thus the cells could be overeating amino acids, perhaps due to a transport error in the membrane. Another patient exhibited "pronounced mental depression". The thought was "slow and sluggish". Again there was "overloading of neurons and cells of astrocyte glia with lipofuscin-like granules". The "mitochondrial cristae were swollen (and sometimes disintegrated)". If the amino acid theory is correct, this would also explain pathology to the mitochondria since amino acids are found in the mitochondria and since many amino acids are capable of being converted to pyruvate, which is used as a substrate by the mitochondria. In this patient the synaptic knobs were abnormal, suggesting a possible neurotransmitter error. "Synaptic knobs contained a large quantity of scattered synaptic vesicles, most of them in the center of the knobs, and only a small number of them around the synaptic membrane, frequently in a state of lysis." The astrocytes "contained an abundant accumulation of structures resembling glycogen". This is further evidence for the amino acid theory. If the cells are flooded with amino acids, they might burn amino acids for fuel instead of glucose. This would cause a backup in glucose metabolism which in turn would probably cause an accumulation of glycogen or something resembling it. Glycogen is a stored form of glucose.

All of this suggests a diet low in amino acids as a treatment. Such a diet would be very strict, much like the diet for PKU.

The Biology of Schizophrenia

This subject is a tangled web of sorts. Nevertheless some brilliant work has been done. Osmond and Smythies proposed a brilliant hypothesis suggesting faulty epinephrine metabolism. Wooley and Shaw proposed a serotonin blockade, but the evidence for this is not convincing. Kety's theory of pathological transmethylation apppears to have been borrowed from Osmond & Smythies. Toxic factors have been reported by Heath, Bergen, and Frohman.

Detroit Work

Peter Beckett and Jaques Gottlieb were brilliant Detroit researchers. They used electrophoresis to analyze blood proteins in schizophrenia. They found two toxic proteins. One produced hemolysis and the other affected the L/P ratio. The L/P ratio was used as a measurement of metabolism. They called one of their proteins "factor 1". Factor 1 delays climbing time in rats. It also raises the amino acid uptake by cells according to Frohman. Factor 2 causes hemolysis.

Heath

Heath's work was very controversial but valuable. He found an anti-septal substance, meaning that the factor attacked the septal area of the brain. Similar work was reported in Russia by Kolaskina.
Conclusions

Beckett & Gottlieb suggested that there may be "more than one kind of schizophrenia". This makes the situation even more complicated. There does appear to be at least one toxic factor, and perhaps more. The toxic factor appears to be made up of amino acids, including methionine. The factor causes amino acids to flood the cells. Thus amino acids appear to be double trouble. Perhpas a diet low in amino acids should be tried. Osmond suggested orthomolecular psychiatry, meaning the use of nutrition. This view was shared by Hoffer and by Pauling.