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UPTAKE OF ALUMINIUM INTO CENTRAL NERVOUSSYSTEM ALONG NASAL-OLFACTORY PATHWAYS

SIR,-Although aluminium (Al) is abundant in the earth’s crustit is not known to be made use of in any natural biological process.Its concentration in the brain is only 2 parts per million,! and theoral administration or subcutaneous injection of Al compoundsresults - in little uptake of the element into the central nervoussystem.2,3 There thus seem to be effective barriers to the entry ofAlinto the brain. We have exposed rabbits to intranasal Al salts andfound evidence of direct uptake into the brain via nasal-olfactorypathways.

A 3 mm hole was drilled in the left paramedian frontal bone ofnine New Zealand rabbits and two strips of ’Gelfoam’ (Upjohn)2 x 3 x 60 mm were inserted in the left nasal recess. The absorbent

sponge was then saturated with 0-5 ml of a solution of 15% Allactate, 5 % Al chloride, or 15 % sodium lactate (three animals each).The animals were observed daily for 4 weeks, and then killed bybarbiturate followed by transcardiac perfusion with a para-

formaldehyde-glutaraldehyde fixative. Brain and spinal cord,lungs, and liver were examined histopathologically. The olfactorybulbs and selected blocks from the cerebral cortex were embeddedin Spurr’s plastic, sectioned, and stained with toluidine-blue forlight microscopy; they were also subjected to laser microprobe massanalysis (Lebold-Heraeus LAMMA 5(0).4

The animals remained free of neurological deficits. The threerabbits exposed to Al lactate had granulomas in the left olfactorybulb and cerebral cortex. The cortical involvement was bilateral butmore severe on the left. Two animals had granulomas in thepyriform cortex and one had a lesion in the hippocampus. Thegranulomas consisted of accumulations of macrophages, lympho-cytes, and occasional plasma cells (figure). On Bielschowski silverimpregnation staining there was no evidence of the neuro-filamentous accumulations found in rabbits after intracerebralaluminium administration. The cerebellum, brainstem, and spinalcord was free of granulomas. A granuloma was identified within thefibre layer of the left olfactory bulb of one of the animals receiving Alchloride, but granulomas were not seen in the cerebral hemispheresof these animals. The animals exposed to sodium lactate were free ofcomparable lesions.

Pyriform cortex from two animals exposed to Al lactate wassubjected to LAMMA and cytoplasmic granules of macrophages inthe granulomas demonstrated a prominent peak at mass 27 (Al).Adjacent neuropil and neurons had no evidence of Al. ProminentAl-related peaks were obtained from cytoplasmic probe sites withinmacrophages present in the olfactory bulb granulomas. Al was alsodemonstrated by LAMMA in macrophages of an olfactory bulbgranuloma of the rabbit exposed to intranasal Al chloride.

When 0 1 ml of a 1 % solution of Al chloride or lactate is injectedinto the subarachnoid space of rabbits, a progressive fatal

encephalopathy is produced, associated with widespread neuro-fibrillary degenerations similar to the neurofibrillary tangles whichare characteristic of Alzheimer’s disease. The rabbits exposedintranasally to Al did not show neurofibrillary changes, perhapsbecause incorporation of the metal within macrophages protects thenervous system from toxic effects. Experiments with long-termolfactory exposure are underway.

We propose that Al can enter the human nervous system througha similar route and that this may explain the accumulation of thiselement in neurofibrillary tangles in Alzheimer’s disease and theGuamanian form of amyotrophic lateral sclerosis and parkinsonismdementia.’

High concentrations of Al and silicon have recently been reportedin the cores of senile plaques in Alzheimer’s disease.8 In Alzheimer’sdisease, Esiri and Wilcock9 have demonstrated involvement of theolfactory bulbs by neurofibrillary tangles and Pearson et al,1O notingthe severe involvement by neurofibrillary tangles and senile plaquesof structures related to the olfactory system, speculated that theagent causing these lesions had entered via an olfactory route.

Histological appearance of granuloma in hippocampus of rabbitexposed intranasally to At lactate.

Haematoxylin and eosin; x 270.

We propose that Alzheimer’s disease involves a defect in the

normally very effective olfactory mucosa/olfactory bulb barriersleading to excessive influx into the brain of Al (and possibly silicon)containing compounds. Aluminosilicates comprise the bulk ofinhaled aerosol contaminants in the air. We recognise that theanimal experiments reported here induced granulomatous lesionswhich are not characteristic of Alzheimer’s disease. Nevertheless,they demonstrate that this route can provide access to the centralnervous system for agents capable of damaging the brain.

We thank Ms J. Kessler and Dr D. Munoz-Garcia for assistance in theearly phases of this work. This study was supported by grant AG-01415 fromthe National Institutes of Health and, in part, by the Sandoz Corporation andthe John Douglas French Foundation.

Neuropathology Division,Department of Pathology,Mount Sinai School of Medicine,New York, NY 10029, USA

DANIEL P. PERLPAUL F. GOOD

1. Crapper DR, Krishnan SS, Dalton AJ. Brain aluminium distribution in Alzheimer’sdisease and especially neurofibrillary degeneration. Science 1973; 180: 511-13.

2. Mayor GH, Keiser JA, Makdani D, Ku PK. Aluminium absorption and distribunon:Effect of parathyroid hormone. Science 1977; 197: 1187-89.

3. DeBoni U, Otvos O, Scott JW, Crapper DR. Neurofibrillary degeneration induced bysystemic aluminium. Acta Neuropathol (Berl) 1976; 35: 285-94.

4. Perl DP, Munoz-Garcia D, Good PF, Pendlebury WW. Laser microprobe massanalyzer (LAMMA): a new approach to the study of the association of aluminiumand neurofibrillary tangle formation. In: Fisher A, Hanin I, Lachman C, eds.Alzheimer’s and Parkinson’s diseases. New York: Plenum Press; 1986: 241-48.

5. Crapper DR, Dalton AJ. Alterations in short-term retention, conditioned avoidanceresponse, acquisition and motivation following aluminium induced neurofibrillarydegeneration. Physiol Behav 1973; 10: 925-33.

6. Perl DP, Brody AR. Alzheimer’s disease: X-ray spectrometric evidence of aluminiumaccumulation in neurofibrillary tangle-bearing neurons. Science 1980; 208: 297-99.

7. Perl DP, Gajdusek DC, Gassuto RM, Yanagihara RT, Gibbs CG Jr. Intraneuronalaluminium accumulation in amyotrophic lateral sclerosis and Parkinsonismdementia of Guam. Science 1982; 217: 1053-54.

8. Candy JM, Klinowski J, Perry RH, et al. Aluminosilicates and senile plaque formationin Alzheimer’s disease. Lancet 1986; i: 354-57.

9. Esiri MM, Wilcock GK. The olfactory bulbs in Alzheimer’s disease. J NeurolNeurosurg Psychiatry 1984; 47: 55-60.

10. Pearson RCA, Esiri, MM, Hiorns RW, Wilcock GK, Powell TPS. Anatomicalcorrelates of the distribution of the pathological changes in the neocortex inAlzheimer’s disease. Proc Natl Acad Sci (USA) 1985; 82: 4531-34.

ANTIBODY-DEPENDENT ENHANCEMENT OFDENGUE 2 VIRUS IN PEOPLE OF WHITE DESCENT

IN CUBA

SIR,-In 1981 Cuba experienced a huge epidemic of dengueserotype 2, with over 300 000 cases and 158 deaths. Unlike the1977-78 outbreak of dengue 1, 1981 saw, for the first time in Cubaor anywhere in the Caribbean, dengue haemorrhagic fever/dengue’shock syndrome (DHF/DSS) in epidemic fonn.1,2