The pathogenesis of Parkinson's disease

Abstract

Until recently, discussions of the pathogenesis of Parkinson's disease depended almost entirely upon clinically derived facts. But since 1960, laboratory data obtained at this Institute, at the University of Montreal (Dr. A. Barbeau), and at the Institute of Pharmacology, University of Vienna (Dr. 0. Hornykiewicz, Dr. H. Bernheimer) have brought about a somewhat changed picture through studies on the metabolism of amines in parkinsonian patients. This novel orientation stems from the contributions of Garlsson and his collaborators, and of Bertler and Rosengren who demonstrated the presence of dopamine in the brain in highly uneven distribution. Sano and his colleagues confirmed this for the human brain, showing that in this organ, also, the dopamine is present in highest concentrations in the basal ganglia and hypothalamus. With this information at hand, it clearly became necessary to investigate whether in parkinsonism there is a defect in the metabolism of dopamine, either centrally or peripherally. Furthermore, with present knowledge of genetic disorders of metabolism, dopamine and other amines have offered a logical focus of investigation in Huntington's chorea. Because of the new information now coming from research laboratories, two recent reviews of the literature1' 2 are to be welcomed. As some of the work described by Dr. A. Barbeau was in collaboration with this correspondent, it will not be inappropriate to note a few emendations. In Dr. Barbeau's article that was recently published in this journal,2 on page 802 it is implied that we measured not only dopamine and dihydroxyphenylacetic acid, but also homovanillic acid. As we are only beginning to measure homovanillic acid in my laboratory, the statement that this metabolite is decreased in the urine of patients with Parkinson's disease cannot be attributed to any work done here. Indeed, I do not know of any published research affirming the statement that homovanillic acid excretion is reduced in parkinsonism. On page 804, it is stated that "it is thought that only the L-isOmer (of dopa) penetrates the blood-brain barrier". The administration of L-dopa in our work3 was based not upon conjecture but upon the demonstration4 that administered L-dopa readily enters the brain, whereas the D-isomer does so only in very limited amounts. On page 806, Dr. Barbeau states that monoamine oxidase inhibitors improve the symptoms of Parkinson's disease, although there is a reference in the text only to tranylcypromine. There are many papers in the literature showing that various MAO inhibitors have different quantitative and qualitative effects in vivo. so that generalizations about a common action in parkinsonism are not valid without many additional clinical data. On the same page, it is stated that "serotonin and nor-adrenaline are better substrates for monoamine oxidase than dopamine". This is part of a statement from which a conclusion is drawn bearing upon the author's proposed hypothesis. However, it has long been established that dopamine is more rapidly oxidized than noradrenaline by monoamine oxidase preparations.5-7 It should be kept in mind that the specific biochemical defect in Parkinson's disease is not known. Given the biochemical results obtained thus far (brain and urinary analyses, dopa-load tests), one can postulate many possibilities: (1) deficient amount of aromatic amino acid decarboxylase (insufficient coenzyme, i.e. pyridoxal phosphate, or subnormal formation of the protein apoenzyme); (2) inefficient binding of dopamine in granules, higher proportion of "free" as against "bound" dopamine, with consequent greater lability of the amine to inactivating enzymes; (3) increased concentrations of monoamine oxidase or catechol 0methyl tranferase; (4) deficient formation of dopa, the precursor of dopamine, from tyrosine. Thus far, only mechanisms (1) (administration of pyridoxine) and (4) (administration of dopa) have undergone trial through forms of "replacement therapy". The fact that dopa does not reverse drug-induced extrapyramidal symptoms is probably due to a difference in neural levels at which biochemical changes occur: in the "natural" disease-at certain basal ganglia, and in the phenothiazine-caused condition-at some other typeof central synapse for which dopa, or one of its products, is an inadequate stimulus. Dr. Barbeau is to be commended for seeking newworking hypotheses as an aid in the clinical and laboratory investigation of parkinsonism. However, the pointsraised in this letter are meant to emphasize that speculative hypotheses should not lose sight of established facts.