Medical Hypotheses 1 Ahdial Hpc4hms (1993) a. 341-343 ~LCQgUMl~UKL*d1993

Is Aluminium an Etiologic Contributor to Alcoholic Amnesia and Dementia?

W. MARVIN DAVIS

309 Faser Hall, University, MS 38677, USA

Abstract-Neurotoxicity from excess brain exposure to aluminium (Al) is well-documented, from both clinical observations and animal experiments, to impair learning, memory and cognition. The etiology of the cognitive impairment in chronic abusers of ethanol-alcoholic amnesia or dementia-is not known, but it is likely to be multifactorial. We hypothesize that a slowly-progressive accumulation of Al in the brain, so as to reach functionally-toxic levels, may be one such factor. This could occur because of an increased permeability of intestinal mucosa to entry of Al, arising from sustained exposure of the gastrointestinal tract to alcoholic beverages, plus a trend for more frequent ingestion of antacids based on Al salts for treating gastritis or ulcers caused by such exposure. If this be true, use of Al-containing medications, as well as all avoidable exposures to Al, should be contra-indicated for chronic heavy drinkers.

Introduction

Among the IO-plus major causes, and many addi- tional minor causes, for the state of brain dysfunc- tion known as dementia, chronic alcohol abuse is a significant component (1). ‘Dementia associated with alcoholism’ is recognized by DSM-IIIR (2) as a psychopathological entity of unknown etiology that is distinct from the ‘Wenicke-Korsakoff syndrome’. The latter is a largely alcoholism-associated condition regarded to be the consequence of a critical nutri- tional deficiency of thiamine (3). A further distinction is that the former is more associated with cortical changes, especially the frontal cortex, and the latter with changes at a subcortical level (4). ‘Amnestic syn- drome’ or subclinical Korsakoff’s syndrome, is the descriptor applied to some less severely affected alco- holics, who still show significant deficits in memory and learning (5).

Date recked 26 April 1993 Date accepted 17 May 1993

Mechanisms for cognitive impairment in alcoholism

There is evidence for multiple mechanisms in the neuropsychological deficits of alcoholic dementia (5, 6). Some putative causes are direct effects of ethanol toxicity, while others are indirect, but all are in- completely understood. A subject of controversy is whether significant cognitive deficits occur in ‘social drinkers’ as well as in persons entering treatment pro- grams for alcoholism (7, 8).

Neurobehavioural toxicity of aluminium

Aluminium (Al) was first recognized as having a po- tential for brain toxicity because of occupational ex- posure through inhalation of dusts (9). The hazard of Al accumulation in brain is highlighted by the con- clusion of GaNOt (10) that normal and lethal lev-

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342 MEDICAL HYF’OTHFSES

els of brain Al differ only by a factor of 3-10, and by his inference that brain-sequestered Al cannot be eliminated readily, if at all. Animal experiments have established that high levels of Al, either injected or taken orally, have neurotoxic properties (11-14).

Much greater attention was focussed on the neuro- toxicity of Al after recognition in 1976 of the dia- lysis encephalopathy syndrome among kidney fail- ure patients, which became known also as ‘dialy- sis dementia’ for cases in whom cognitive and be- havioural changes predominated. Elevated levels of Al in serum, muscle, bone and brain were found in such patients as a consequence of their inability to excrete the Al overload often incurred because of in- creased exposure in the course of their treatment (15, 16).

A rigorous study of 35 hemodialysis patients (17) found higher Al levels (estimated body burden) to be associated with greater impairment of visual mem- ory, while measures of frontal lobe function, atten- tion/concentration, depression and other neurocogni- tive scores were inversely proportional to Al lev- els among those patients having lower scores for pre-morbidity intelligence. This finding of deficits in frontal lobe function agrees with cerebral com- puter tomographic findings in dialysis patients show- ing greater cortical atrophy in the frontal lobes (18).

The inferences of human neuropsychological injury arising from Al were supported recently by the serial assessment of cognitive status in 10 persons affected by an accidental severe contamination of the drink- ing water supply of an English community by alu- minium sulfate (19). Consistently there was evidence for impairment of verbal fluency, memory and infor- mation processing, which hampered their maintaining employment and coping generally. Such deficits and consequent problems persisted to 8-26 months past the accident.

Influences on absorption of aluminium

Research on factors affecting gastrointestinal absorp- tion of Al has focussed largely on various dietary components, but particularly organic acids (20). Cit- ric acid was found repeatedly to enhance Al ab- sorption (e.g. (21, 22)). Moreover, intestinal atrophy induced in rats by difluoromethylomithine treatment (23), which constituted a model of the atrophy of in- testinal mucosa in human uremia, caused absorption of an oral dose of Al to be enhanced. A similar in- crease of serum Al levels occurs in uremic patients without dialysis, although less extreme than for dial- ysis dementia patients (16).

It has been shown that chronic intake of ethanol @OH) damages the integrity of the intestinal bar-

rier in rats, so that even macromolecules can have enhanced access to the blood by passive diffusion across the intestinal mucosa (24). Thus, it appears possible that uptake of aluminium salts might also be increased. Similar studies on permeability of the intestinal mucosa of alcoholics (25) have begun, but they have not dealt with Al absorption. We recog- nize that most reported deviations of intestinal trans- port of micronutrients-vitamins and minerals-are toward impaired uptake. However, tissue levels of metals tending to be depleted by chronic ethanol intake--especially magnesium, because ethanol is a potent Mg diuretic (26), but also calcium (27). zinc, copper, and others (28)-may enhance the uptake of Al from the GI tract. Rats fed diets that contained suboptimal levels of zinc or copper showed a greater accumulation of Al in brain tissues than controls (29); Al increased 3-fold in the frontolateral cortex and 8- fold in the hippocampus, brain areas vital to human memory and cognition. Absorption and retention of Al by rat intestine also were increased by a reduced calcium level in the diet and in the gut (30).

Ethanol-aluminium inter-relationships

Certain findings among those indicated above led us to hypothesize that chronic oral EtOH exposure, e.g. in human alcoholics, might amplify the normally-low level of Al uptake from the GI tract and make it available for accumulation to an effective level in the brain. A literature search revealed that a test of this hypothesis at the animal level had already been supplied recently by Flora and co-workers (31), al- though their study apparently stemmed from another rationale. They found that daily oral administration of 25 mg_/kg of aluminium nitrate, along with 10% EtOH (v/v) in drinking water, produced significantly higher serum Al levels than did the same dose of Al in rats without EtOH. The rats receiving Al and EtOH together for 6 weeks also had an amplified depletion of brain dopamine and serotonin compared to those with Al alone (31). This regimen of EtOH alone did not alter brain biogenic amine levels, but the effect of Al on brain monoamines seems likely to interact with actions of EtOH on neurobehavioural parameters. Ob- servations in a human alcoholic population would be desirable as a further test of our hypothesis.

Conclusions

Because of the gastritis, and even ulcers, often in- curred by alcohol abusers (32), they are prone to in- gest greater amounts of gastric anatacids than other persons. Most OTC antacid products as well as a popular prescription treatment for peptic ulcer, sucral-

AL-M AND ALCOHOLIC AMNESIA AND DEMENTIA

fate, are based upon Al salts or complexes. There- fore, high-level Al ingestion is more likely for alco- hol abusers. The theoretical analysis by Ganrot (10) indicated that extra exposure to Al via antacids should produce appreciable elevation of brain Al without an increased rate of GI absorption. The rat data of Flora et al (31), suggesting an enhancement of Al absorp- tion by ethanol, thus support the inference that there is a high probability that Al ingestion and its uptake from the intestinal tract may also be elevated in alco- holics compared to non-alcoholics. We are unaware of any available measures relative to this issue.

The implications of this hypothesized excess Al intake, absorption and brain accumulation, regarding brain function of alcohol abusers, are especially omi- nous considering the likely exposure of such persons to other factors tending to damage cognitive func- tions. The waming of Bolla et al (23) with respect to dialysis patients seems applicable also to chronic al- cohol abusers-that Al ‘has neurotoxic properties and its reduction in medications...and in the environment is critical’.

Acknowledgements

This work was suppotted by the Research Institute of Phamtaceu- tical Sciences, ‘Ilte University of Mississippi.

References

1.

2.

3.

4.

5.

6.

1.

8.

9.

10.

11.

Fraser M. Dementia: Its Nature and Management. New York: John Wiley & Sons. 1987. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Third Edition. Revised. Wash- ington DC: Am Psychiat Assoc. 1987. Bhxss 1, Gibson G. Abnormality of a thiamin-requiring enzyme in uatients with Wemicke-Korsakoff svndrome. New Enel J M&l 1977; 297: 1367-1370. ’

Y

Victor M, Iaureno R. Nemologic complications of alcohol abuse: Epidemiologic aspects. Adv Nemo1 1978; 19: 603-617. Tarter R E et al. Neurobehavioural disorders associated with chronic alcohol abuse. In: Goedde H W, Agarwal D P, eds. Al- coholism: Biomedical and Genetic Aspects. New York: Perg- amon Press, 1989: 113-129. Tatter R E, Edwards K L. Multifactorial etiology of neuro- psychological impairment in alcoholics. Alcoholism: Clin Exp Res 1986; lo: 128-135. Parker D A et al. Alcohol use and cognitive loss among employed men and women. Am J Public Health 1983; 73: 521-526. Parsons 0 A. Cognitive functioning in sober social drinkers: A review and critique. J Stud Ale 1986; 47: 101-114. McLaughlin A I G et al. Pulmonary fibrosis and encephalopa- thy associated with the inhalation of aluminium dust. Br J In- dust Med 1962; 19: 253-263. Ganrot P 0. Metabolism and possible health effects of alu- minium. Environ Health Perspect 1986; 65: 363441. Crapper D R, Dalton A J. Alterations in short-term retention,

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

343

conditioned avoidance acquisition and motivation following aluminum induced neurofibrillary degeneration. Physiol Be- hav 1973; 10: 925-933. Yokel R A. Repeated systemic aluminum exposure effects on classical conditioning of the rabbit. Neurobehav Toxic01 Ter- atol 1983; 5: 414. Berlyne G M et al. Aluminum toxicity in rats. Lancet 1972; i: 564-568. Marquis J K. Aluminum neurotoxicity. An experimental per- spective. Bull Environ Contam Toxic01 1982: 29: 43-49. Alfrey A C et al. The dialysis mcephalopathy syndrome: Pos- sible aluminum intoxication. New Engl J Med 1976; 294: 184-188. Sideman S, Manor D. ‘Ihe dialysis dementia syndrome and aluminum intoxication. Nephron 1982; 31: l-10. Bolla K I et al. Neurocognitive effects of aluminum. Arch Neurol 1992; 49: 1021-1026. Cusamo F, Savazzi G. Cerebral computed tomography in ure- mic and hemodialymd patients. J Comput Assist Tomogr 1986; 10: 567-570. McMillan TM et al. Camelford water poisoning accident: Se- rial neuropsychological assessments and further observations on bone aluminium. Hum Exp Toxicol 1993; 12: 37-42. Domingo J L et al. Influence of some dietary constituents on aluminum absorption and retention in rats. Kidney Int 1991; 39: 598-601. Cobum J W et al. Calcium citrate markedly enhances alu- minum absorption from aluminum hydroxide. Am J Kidney Dis 1991; 17: 708-711. Walker J A et al. The effect of oral bases on enteral aluminum absormion. Arch Intern Med 1990: 150: 2037-2039. Ittel T H et al. Induction of intestinal mucosal atrophy by di- Ruoromethylomithine: A naturemic model of enhanced alu- minum absorption. Miner Electr Metab 1992; 18: 15-23. Worthington-Roberts B. Changes in intestinal passive perme- ation induced by alcohol. In: Stock C, Bode J C, Sarles H, eds. Alcohol and the Gastrointestinal Tract. Editions INSERM, vol 95, 1980: 507-518. Tiemey L et al. Effect of acute and chronic ethanol on intesti- nal permeability in man. FASEB J 1993; 7(4): A843. Bush B. Management of the alcoholic inpatient. In: Barnes H N, Anmsat M D, Delbanco T L, eds. Alcoholism: A Guide for the Primary Care Physician. New York: Springer-Verlag. 1987: 83-89. Cyr M G. Moulton A W. The gastrointestinal tract and pan- creas. In: Barnes H N, Aronson M D, Delbanco T L, eds. Al- coholism: A Guide for the Primary Care Physician. New York: Springer-Verlag 1987: 127-133. Bogden J D et al. Effect of chronic ethanol ingestion on the metabolism of copper, iron, manganese, selenium, and zinc in an animal model of alcoholic cardiomyopathy. J Toxic01 Environ Health 1984; 14: 407417. Wenk G L, Stemmer K L Suboptimal dietary zinc intake in- creases aluminum accumulation into the rat brain. Brain Res 1983; 288: 393-395. Provan S D, Yokel R A. Reduced intestinal calcium and di- etary calcium intake, increased aluminum absorption, and tis- sue concentration in the rat. Biol Trace Elem Res 1989-a 23: 119-132. Flora S J S et al. Effects of combined exposure to aluminlnn and ethanol at aluminum body burden and some neuronal. hepatic and haematcpoietic biochemical variables in the rat. Hum Exp Toxic01 1991; 10: 45-48. Mendelson J H, Mel10 N K. Alcohol: Use and Abuse in Amer- ica. Boston: Little, Brown and Co., 1985: 210-211.