It is generally accepted that senile dementia of the Alzheimer type, the most common form of dementia with late onset, should be considered as a multifactorial condition, in which a variety of causative factors are involved, such as genetic factors, toxic- metabolic-nutritional factors, vascular factors and depression-related factors. I am putting forward the hypothesis that variable interaction of the above mentioned factors results in altered activity of microsomal P-450 liver enzyme systems. For an enlightening review on microsomal liver enzyme function see Conney (l986).

The altered microsomal liver enzyme function can result in increased levels of Ammonia in blood, described in SDAT. It will also result in alterations in drug metabolism, due to changes in toxifying and detoxifying capacity of the liver, whilst changes in metabolism of endogenous substances such as thyroid-hormones and steroid-hormones can be observed as well. There is abundant literature indicating that alterations in microsomal liver enzyme function has a profound effect on the biological availability of nutrients such as trace-elements, vitamins and amino acids. I refer here in particular to the nutritional data collected in patients with well known altered microsomal liver enzyme status such as chronic phenylhydantion users and chronic alcoholics: selective nutritional deficiencies in the central nervous system have been described in these groups, in my opinion caused by defective activation in the affected liver of the processes that convert certain vitamins into the form with access through the blood-brain barrier and/or plexus chorioideus to the central nervous system: this problem arises in particular with vitamin B1, vitamin B12, and with folic acid.

Extensive evidence of compromised vitamin B1, vitamin B12 and folate status in relation to neuropsychiatric pathology is available, to some extent even documenting cerebral deficits of these vitamins in SDAT. Animal experiments have shown profound neurotransmitter changes in the brain of animals made deficient in vitamin B12, vitamin B1, and folate, including considerable reduction of Acetylcholine levels, a crucial finding in SDAT.

Recently much attention has been given to the possible role of glutamic acid as a neurotoxic agent contributing to the development of typical Alzheimer neuropathology. Increase in glutamic acid levels can be secondary to the altered microsomal liver enzyme activity and hyperammonaemia, which influences strongly levels and access of amino-acids (precursors of neurotransmitters) to the brain, in that way influencing brain function, whilst it also influences access of other potentially neurotoxic amino acids such as quinolinic acid and homocysteine. Glutamic acid neurotoxicity is strongly potentiated by neuronal hypoxia, whilst the combined neurotoxic effect of glutamic acid and hypoxia can be modified by zinc, glutamine and taurine.

These considerations open up a perspective for a potentially effective preventive nutritional strategy in dementing disorders: application of the suitable forms of parenteral vitamin B1, vitamin B12, folic acid and taurine, supported by oral administration of a balanced trace-element preparation containing zinc, selenium, molybdenum, iodine, traces of manganese and copper, iron, magnesium, calcium, chromium, boron and glutamine. In my clinical experience this combination appears to be very effective, resulting in arresting dementia-syndromes and improving conditions of alcohol or other toxic chemical induced neuropsychiatric pathology (van Tiggelen l987).
Neurotoxicity of glutamic acid in SDAT, its modulation by zinc, taurine, glutamine Recently the neurotoxicity of the excitatory amino acid glutamic acid has been suggested as being involved in the development of senile dementia of the Alzheimer type and possibly in other organic mental disorders (Greenamyre 1986, Greenamyre 1988. Hardy 1987, Cross 1987). Convincing evidence is available demonstrating that the neurotoxicity of glutamate is strongly potentiated by neuronal hypoxia (Jorgensen 1982, Simon 1984, Schwartz l985, Rothman 1986, Petito l986, Nehls 1988), whilst a potentiating effect of corticosteroids is also possible (Sapolsky 1985). The potentiating hypoxia can be of cardiovascular or cerebrovascular origin, in this respect a recent publication (Brun 1986) deserves attention. The neuronal hypoxia can also be of metabolic origin, eg. secondary to metabolic disturbances in cerebro as in vitamin B1, deficiency (Hirsch 1984, Gibson 1988).

Glutamate neurotoxicity can be modified by specific ions (Olney 1986), in particular the trace element zinc can play a modulating role (Peters l987, Koh 1988).This is interesting against the background of observation on the role of zinc in alcohol-related dementia syndromes (van Tiggelen l979, Kasarskis l985) and rekindles the potential role of zinc in senile dementia (Burnet l981). The study of alcohol-induced encephalopathy as a model for the study of senile dementia of the Alzheimer type, originally suggested by Burnet (personal communication) will appear to be far more fruitful than assumed in particular in regard to the possible involvement of subtle and sub-clinical liver dysfunction caused by altered microsomal liver enzyme activity and resulting in hyperammonaemia and secondary nutritional deficiencies in cerebro. In this respect the favourable results of oral zinc supplementation in patients with alcohol induced encephalopathy (Reding 1984) deserve duplication.

Furthermore a protective role against neuronal hypoxia (a factor strongly potentiating neurotoxicity of excitatory amino acids) can be attributed to the amino acid glutamine (Schurr l987a) and to the amino acid taurine (Schorr l987b). The interaction between taurine and excitatory amino acids is extensively studied (Lehmann l987 and ref there), but more indications are coming forward that taurine plays a protective role in particular in highly excitable tissue of nervous origin (Lake 1986), supporting clinically interesting observations in the Japanese literature in the use of taurine in cardiovascular pathology, which favourable clinical experiences with taurine will find probably more application in cerebral pathology when a lipophilic taurine-derivative such as MYll7 (Oja 1982) can be applied parenterally. Summarized: glutamate neurotoxicity seems to play a role in SDAT, and most likely in other chemical induced organic mental syndromes and dementia syndromes, such as alcohol related brain damage, solventia dementia and industrial chemical induced neurasthenia.

Neuronal hypoxia plays a potentiating role and should be minimalized by optimizing cardiovascular, cerebrovascular and blood-viscosity status. A combination of zinc-ions, taurine and glutamine may provide considerable protection against the combined neurotoxic effect due to excitotoxicity and hypoxia. The role of vitamin B12 in SDAT considering a role for folic acid in biological activation of vitamin B12. Extensive information is available in the literature on compromised vitamin B12 status in patients with SDAT: Inada l982 described reduced levels of vitamin B12 in brain tissue of dementia sufferers, van Tiggelen (l984a, 1984b) described reduced levels Of Vitamin B12 in the cerebrospinal fluid of SDAT patients, notwithstanding normal serum levels. Later vitamin B12 anomalies in SDAT patients were described by other groups (Cole 1984, Karnaze and Carmel l987), increasingly the picture is becoming clear that the biological availability of vitamin B12 can be compromised resulting in neuropsychiatric pathology in the absence of haematological pathology (Kanazawa l985, Herbert 1988, Carmel l988a, Carmel l988b, Hallam l987, Levitt l988).

It may well be that indeed the only form of vitamin B12 in the central nervous system with biological activity is methylcobalamine (Goto 1987), which is possibly also the biologically active component in the immune system (Kubota 1987, Takimoto 1982) and in osteoblasts (Carmel 1988c) which raises the possibility that methyl-cobalamine deficiency can result in reduced intestinal alkaline phophatase levels interfering with intestinal absorption and possibly biological activation of vitamin B1, (Schaller 1975).

In this respect the interaction between vitamin B12 and folic acid should be mentioned (Stokstad 1988) (Botez 1979, Figueroa 1980, Botez 1982a, Botez 1982b), which could suggest a role for folic acid or rather methyl-tetra-hydro-folate in the conversion of cobalamine in the biologically highly active form of methyl-cobalamine. This concept is supported by clinical observations in patients with folate responsive neuro-psychiatric pathology who showed improvement in vitamin B12 status after being medicated with folic acid. It has been demonstrated that cerebral vitamin B12 deficiency has profound effects on neurotransmitter levels in cerebro in animal experiments (Deana 1977, Hakim l983) affecting Noradrenaline and Acetylcholine levels as well as regional glucose utilization. Summarized, there seems to be an indication that in SDAT and possibly a variety of organic mental disorders the biological activity of vitamin B12 is impaired in the central nervous system, possibly due to reduced availability of methyl-cobalamine, which may be associated with complex folic acid abnormalities. The possibility that a functional vitamin B12 deficiency can interfere with vitamin B1 absorption, transport and biological activity should not be underestimated.

The role of vitamin B1, in SDAT.
Recently attention has been drawn to the defective thiamine status, presenting as defects in vitamin B1, dependent enzymes, in the brains of patients with senile dementia of the Alzheimer type (Blass l988, Gibson 1988, Kwan-Fu Rex Sheu l988). Therapeutic trials with oral thiamine in demented patients were ineffective. This may be due to malabsorption of the oral thiamine or inability of the conversion in the liver of thiamine in the form which passes readily the blood-brain barrier of the dementia patients. It has been demonstrated (Baker l983) that fat-soluble allithiamines (Thomson 1971) are better absorbed and penetrate into the CNS compartment far more readily: the components suggested are thiamine-propyl-disulphide and thiamine-tetrahydrofurfuryl-disulphide. However biological activity of these components is most likely dependent on liver function, as suggested by Oda (1984). Deficiency of biologically active thiamine in the brain is associated with a wide range of neuropathology in cerebro, as is known from study of the brains of chronic alcoholics. It has been suggested (Gibson 1988) that vitamin B1, deficiency in cerebro can contribute to the neurotoxicity of glutamate by contributing to tissue hypoxia and in disturbing the balance between glutamic acid and glutamine. Furthermore it has been demonstrated that cerebral B1, deficiency results in a considerable reduction of acetylcholine levels in the brain (Heinrich l973), whilst interaction with other transmitters has been noticed (Freye l982), as reported by Florence (l988) involving reduction of dopamine levels in case of thiamine deficiency due to the role of thiamine in the blockade of dopamine oxidation to by hydroxy-dopamine, which in itself is a neurotoxic agent for the noradrenergic neurons in the locus coeruleus and in the dorsal noradrenergic bundle.

This indicates a possible therapeutic or rather preventive role for application of parenteral thiamine or parenteral allithiamine in an endeavour to correct thiamine function in cerebro, which may have a beneficial effect in SDAT and in a variety of other neuro-psychiatric disorders such as several dementias, tardive dyskinesia, manifestation of manganese toxicity (Florence l988), minimal brain dysfunction in children, toxic neuromyeloencephalopathy, Gille de la Tourette syndrome, posttraumatic stress disorder, stress related psychosomatic diseases, immune disorders, chemical allergies, myalgia encephalopathica, depressive disorders, osteoporosis. Most likely parenteral vitamin B1, parenteral vitamin B12, parenteral folic acid have to be combined in parenteral application in a physiological dose, possibly in combination with the lipophilic taurine, whilst support by a glutamine-based well balanced trace element preparation containing minimal amounts of copper and manganese, but twice the recommended daily allowance of zinc, selenium, molybdenum, chromium, iodine and substantial amounts of calcium, magnesium (as Phosetamin) and iron and vitamin C, may increase the therapeutic effectiveness. The main aim of the supporting trace element preparation is to normalize the altered microsomal liver enzyme activity. And this preparation may even facilitate suppression of genetic predisposition to alterations of microsomal liver enzyme function under otherwise inducing circumstances.

References