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CALCIUM AND ALZHEIMER’S DISEASE

SiR,—West’ 1 suggested that the presence of aluminium silicates inthe plaques of Alzheimer’s disease might be secondary to calciumdeficiency. We have also suggested that the concentration of

aluminium and silicon within plaques might be a secondary process(March 15, p 619), and we agree with Dr Candy and his colleagues(Feb 15, p 354) about the importance of calcium in elderly people.We hypothesise that chronic low calcium levels or frequent changesin the calcium flux increases the likelihood of plaque andneurofibrillary tangle (NFT) formation and that this in turn willdisrupt the formation of memories. We have based our hypothesison the following observations:(1) the level of calcium is a major, if not the major, influence on

microtubule assembly/disassembly;2 2(2) the NFTs in senile dementia of the Alzheimer type (SDAT)

seem to represent disordered assemblies ofmicrotubules;3,4(3) microtubules are closely related in structure, development, and

functioning to postsynaptic densities that are involved in senileplaques (March 15, p 619); and

(4) calcium deficiency occurs5,ó in a range of diseases (SDAT,parkinsonian dementia of Guam, amyotrophic lateral sclerosis,and Down’s syndrome) in which NFTs and plaques are a

neuropathological feature of the illness.We have argued that the formation of memories involves the

specific grouping of microtubules, and that the disruption of theseassemblies results in disorders of learning and memory. Oldermemories, being more widely represented throughout the brain,will be less vulnerable than newer memories to the disruption of thetransport system within any one cell. Our test of the hypothesis thatSDAT patients would show a positive correlation between calciumlevel and cognitive score has revealed that when age, diet, vitamin Dlevels, and renal function are controlled, calcium levels are lower inmoderate to severe SDAT than in mild SDAT patients8 .We suggest that attention to calcium level and, perhaps, calcium

supplementation, will provide some protection against cognitivedecline in Alzheimer’s disease and also in benign senescence.

Department of Psychology,University of Edinburgh,7 George Square,Edinburgh EH8 9JZ

Pulse Train Technology,Esher

IAN J. DEARY

A. E. HENDRICKSON

1 West RD Aluminosilicates and Alzheimer’s disease. Lancet 1985; ii: 682.2 Yamamoto H, Fukunaga K, Goto S, et al. Ca2 +, calmodulin-dependent regulation of

microtubule formation via phosphorylation of microtubule-associated protein 2, &tgr;

factor and tubulin and comparison with cyclic AMP-dependent phosphorylation JNeurochem 1985; 44: 759-68.

3 Grundke-Iqbal I, Johnson AB, Wisniewsky HM, et al. Evidence that Alzheimer

neurofibrillary tangles originate from neurotubules. Lancet 1979, i: 578-804 Kosik KS, Duffy LK, Dowling MM, et al. Microtubule associated protein 2:

Monoclonal antibodies demonstrate the selective incorporation of certain epitopesinto Alzheimer neurofibrillary tangles. Proc Natl Acad Sci USA 1984; 81: 7941-45.

5 Gajdusek DC. Hypothesis Interference with axonal transport of neurofilament as acommon pathogenic mechanism in certain diseases of the central nervous system. NEngl J Med 1985, 312: 714-19.

6. Barlow PJ, Sylvester PE, Dickerson JWT. Hair trace metal levels in Down syndromepatients. J Ment Def Res 1981; 25: 161-69

7. Hendrickson AE. The biological basis of intelligence. Part one. theory. In Eysenck HJ,ed A model for intelligence. New York: Springer, 1982. 151-96.

8. Deary IJ, Hendrickson AE, Burns A. Serum calcium levels in Alzheimer’s disease: Afinding and an aetiological hypothesis Pers Individ Diff(in press).

ANIMAL MODEL FOR NEPHROTOXICITY OFHAEMOGLOBIN TETRAMER

SIR,-As your March 29 editorial notes, the nephrotoxicityof haemoglobin solution has to be tackled before further clinicaltests can be done. For example, the most recent trial in man withtetrameric haemoglobin solution1 demonstrated that infusedtetramer produced gross haemoglobinuria plus a major buttransient decline in glomerular filtration rate and urine volume.This product was not nephrotoxic in animal models, and youreditorial failed to point out that published animal models havenot reliably predicted the renal dysfunction subsequently notedin clinical trials. We have developed a sensitive primate model

INDICES OF RENAL FUNCTION IN BABOONS INFUSED WITH

RINGER’S LACTATE OR TETRAMER

*p=0 05 (change in tetramer vs change in Ringer’s lactate).to = 0 -08 (change in tetramer vs change in Ringer’s lactate).

for tetramer nephrotoxicity. Well-hydrated baboons wereinfused with Ringer’s lactate or tetramer at a rate of 15 ml/kgover one hour, with the results shown in the table.This is the first report of an animal model that produces a

positive control for the nephrotoxicity of the stroma-freetetramer.

Also, we have refined pyridoxylated polymerisedhaemoglobin solution with a view to eliminate nephrotoxicity.2The current modification (Northfield Laboratories) has a

weight-averaged molecular weight of 120 000 and should be toolarge to be filtered by the kidney. The absence of nephrotoxicityor haemoglobinuria with this polymeric haemoglobin solutionwould represent a major advantage over other haemoglobinpreparations.

Department of Surgery,Michael Reese Hospital,and Medical Center

Chicago, Illinois 60616, USA

GERALD S. MossSTEVEN A. GOULDARTHUR L. ROSENLAKSHMAN R. SEHGALHANSA L. SEHGAL

1. Savitsky JP, Doczi J, Black J, Arnold JD. A clinical safety trial of stroma-freehemoglobin. Clin Pharmacol Ther 1978; 23: 73-80.

2. Sehgal LR, Rosen AL, Gould SA, Sehgal HL, Moss GS. Preparation and invitrol characteristics of polymerized pyridoxylated hemoglobin. Transfusion1983; 23: 158-62.

QUETELET INDEX AS INDICATOR OF OBESITY

SiR,-Dr Macdonald (May 3, p 1043) reports that the fat-free mass(FFM) among 150 men with a weight of70-71’9 9 kg ranged fromabout 54 kg to 64 kg. Some of this variation will be due to error in themethod used to estimate fat, and hence FFM. However, sheconcludes that Quetelet’s index (W/H2) "is of little value whenassessing obesity in individuals ... Where possible alternativemethods for measuring fat content should be used."We have used the three best methods for determining body fat

(body density, total body water, and total body potassium) in a seriesof 104 female and 24 male subjects who ranged from about 6% to60% fat.1 Differences in fat content explained about 90% of thevariation in weight-for-height in these individuals. If the average ofall three methods is taken to be the "true" body fat for eachindividual, the standard deviation of the estimates from this "true"value among men and women, respectively, was: for density, 5 - 8 kgand 3 - 4 kg; for water, 3 - 8 kg and 3 - 3 kg; for potassium, 4 - 1 kg and3-5 5 kg; for W/H2, 5-8 8 kg and 4-2 2 kg. Thus W/H was nearly asgood for measuring body fat as these expensive laboratory methods,which are themselves not without error.

Weight and height can be measured easily and accurately, andW/Hz gives a fairly good estimate of obesity. A change in weightindicates the progress of an obese patient under treatment quitewell. If the response to treatment is judged by the change in anestimate of fatness which has an error of several kg of fat this willcause unnecessary distress to both patients and doctors.

MRC Clinical Research Centre,Harrow, Middlesex HA 13UJ J. S. GARROW

1 Garrow JS, Webster J. Quetelet’s index (W/H2) as a measure of fatness. Int J Obesity1985; 9: 147-53