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INCREASED CEREBRAL VENTRICULAR VOLUME IN MONOZYGOTIC TWINS DISCORDANT FOR ALCOHOLISM
986
INCREASED CEREBRAL VENTRICULAR VOLUME IN MONOZYGOTIC TWINS DISCORDANT FOR ALCOHOLISM
careful zinc monitoring should be applied to all patients who show low FTS activity. The possibility of dietary zinc supplementation should be investigated. The measurement of FTS activity by bioassay before and after addition of zinc salts to plasma samples could help in identifying those who might benefit from such
supplementation. This work, done within the framework of EURAGE, was supported by a grant from Consiglio Nazionale delle Ricerche CT81.00196.04 and by a grant from the Progetto Finalizzato Medicina Preventiva e RiabilitativaSottoprogetto Meccanismi di Invecchiamento to N. F., and by grants 8101371961 and 82.02174.56 to C. F., within the Progetto Finalizzato sul Controllo della Crescita Neoplastica-Sottoprogetto Controllo Immunologico and within the Progetto Finalizzato Medicina Preventiva e RiabilitativaSottoprogetto Meccanismi di Invecchiamento respectively. We thank Dr A. Bernardini and Dr M. Mariottini of Laboratorio di Igiene e Profilassi of Ancona for the zmc determination and Mrs Nazzarena Gasparini for her excellent technical assistance.
Correspondence should be addressed to N. F., Department, Via Birarelli 8, 60100 Ancona, Italy.
INRCA Research
REFERENCES
T, Kay Age influence on the immune system. Adv Immunol 1980; 29: 287-330. 2. Licastro F, Chiricolo M, Tabacchi P, Parente R, Cerici M, Barboni F, Franceschi C. Defective self recognition in subjects of far advanced age. Gerontology 1983; 29: 64-72. 3. Levin S, Schlesinger M, Handzel Z, Hahn T, Altman Y, Czenobisky B, Boss Y. Thymic deficiency in Down’s syndrome. Pediatrics 1979; 63: 80-84. 4. Walford RL, Naeim F, Hall KY, Tam CF, Gatti RA, Medici M. Accelerated aging in Down’s syndrome: the concept of heirarchical homeostasis in relation to local and global failure. In: Fabris N, Garaci E, Hadden J, Mitchison NA, eds. Immunoregulation. London: Plenum Press, 1983: 399-417. 5. Franceschi C, Licastro F, Paolucci P, Masi M, Cavicchi S, Zannotti M. T and B lymphocyte subpopulations in Down’s syndrome. A study on non-institutionalized subjects. J Ment Defic Res 1983; 22: 179-91. 6. Martin GM. Genetic and evolutionary aspects of aging. Fed Proc 1979; 38: 1962-67. 7. Singh V, Singh AK. Age-related changes in human thymus. Clin Exp Immunol 1979; 37: 507-17. 8. Fabris N, Pierpaoli P, Sorkin E. Lymphocytes, hormones and ageing. Nature 1972; 240: 557-59. 9. McClure JE, Goldstein AL. Changes with age in blood levels of thymosin &agr;1 as measured by radioimmunoassay. (Abstr). 4th International Congress of Immunology, Paris, 1980; 17:2.26. 10. Bach JF, Dardenne M, Papernik M, Barois A, Levasseur P, Le Brigand H. Evidence for a serum factor produced by the human thymus. Lancet 1972; ii: 1056-58. 11. Lewis VM, Twomey JJ, Beahmear P, Goldstein G, Good RA. Age, thymic involution and circulating thymic hormone activity. J Clin Endorcinrol Metab 1978; 47: 145-50. 12. Franceschi C, Licastro F, Chiricolo M, Bonetti E, Zannotti M, Fabris N, Mocchegiani E, Fantini MP, Paolucci P, Masi M. Deficiency of autologous mixed lymphocyte reactions and serum thymic factor level in Down’s syndrome. J Immunol 1981; 126: 2161-64. 13. Weksler ME, Innes JB, Goldstein G. Immunological studies of aging. IV. The contribution of thymic involution to the immune deficiencies of aging mice and reversal with thymopoietin. J Exp Med 1978; 148: 996-1006. 14. Savmo W, Dardenne M, Papiernik M, Bach JF. Thymic hormone-containing cells. Characterization and localization of serum thymic factor in young mouse thymus studied by monoclonal antibodies. J Exp Med 1982; 156: 628-33. 15. Oosterom R, Kater L. Human thymic epithelial conditioned medium; biological activity and its similarity to thymosin. In: Aiuti F, Wigzell H, eds. Thymus, thymic hormones and T lymphocytes. London: Academic Press, 1980: 245-55. 16. Bach JF. Thymic hormones, their role in T cell differentiation, regulation of immunity and aging. In: Proceedings of Vth International Congress of Immunology. NorthHolland: Excerpta Medica, (in press). 17. Editorial. Lancet 1983; i: 1309-11. 18. Bach MA, Beauram G. Respective influence of extrinsic and intrinsic factors on the age-related decrease of thymic secretion. J Immunol 1979; 122: 2505-07. 19. Dardenne M, Savino W, Gastinel LN, Nabama B, Bach JF. Thymic disfunction in the mutant diabetic (db/db) mouse J Immunol 1983; 130(3): 1195-99. 20. Dardenne M, Pleau JM, Nabama B, Lefancier P, Denien M, Choay J, Bach JF. Contribution of zinc and other metals to the biological activity of the serum thymic factor. Proc Natl Acad Sci USA 1982; 79: 5370-73. 21. Ohga K, Incefy GS, Fok KF, Erickson BW, Good RA. Radioimmunoassays of the 1. Makinodan
thymic hormone serum thymic factor (FTS). J Immunol Methods 1983; 57: 171-84. JM. Current knowledge on zinc, copper and chromium in aging. Wid Rev Nutr
24.
25.
Diet 1979, 33: 42-69. Bjorksten B, Back O, Gustavson KH, Hallmans G, Hagglof B, Tornvik A. Zinc and immune function in Down’s syndrome. Acta Pediatr Scand 1980; 69: 183-87. Fernandez FJ, Kahn HL. Clinical methods for atomic absorption spectroscopy. Clin Chemistry Newsletter 1971; 3: 24-28. Pleau JM, Dardenne M, Blanot D, Bricas E, Bach JF. Antagonist analogues of serum thymic factor (FTS) interacting with the FTS cellular receptor. Immunol Lettrs
1979; 1: 179-82. 26.
Genetics Section,
Department of Psychiatry, Institute of Psychiatry, University of London, De Crespigny Park, London SE5 8AF
pairs of monozygotic twins discordant for and heavy drinking were examined by computerised tomography. Brain and ventricular volumes were calculated by the use of a semiautomated method with the rater blind to twinship and drinking history. 11 severely dependent alcoholics had larger Summary
21
alcoholism
ventricular volumes and ventricle/brain ratios than did their normal cotwins. These changes correlated best with the length of time the alcoholic twin had been drinking eight centilitres pure alcohol, equivalent to a bottle of wine, a day.
MMB.
22. Hsu 23.
H. M. D. GURLING MICHAEL A. REVELEY R. M. MURRAY
Chandra RK, Dayton DH. Trace element regulating immunity and infection. Nutr Res 1982; 2: 721-33.
27. Fraker PS. Zinc deficiency: 1983; 2: 155-63
a common
immunodeficiency
state.
Surv Immunol Res
Introduction ALCOHOLISM has been found to cause enlarged ventricles and widened cortical sulci.1 The changes, which are partly reversible,2 correlate with the length of time an alcoholic has been abstinent before CT scanning.’ The abnormalities represent a reduction in the volume of brain substance and correlate to a variable extent with psychological deficits in abstract reasoning and tactual performance.3 The twin method offers the considerable advantage of controlling perfectly for genetic predisposition and age. We have examined whether the alcoholic or heavy drinking member of a discordant identical twin pair has detectable ventricular abnormality, and whether any change found is related to
dependence or merely to heavy drinking. Methods
Selection
of Patients
pairs of monozygotic twins discordant for drinking behaviour recruited from a variety of sources, mainly the Maudsley Hospital twin register, which yielded 11 pairs in which one member met the World Health Organisation criteria for the alcohol dependence syndromes4—namely, increased tolerance to alcohol; repeated withdrawal symptoms; repeated relief or avoidance of withdrawal symptoms by further drinking; subjective awareness of a compulsion to drink; and reinstatement of the syndrome after 21
were
abstinence. The second group of 10 pairs of twins, known as the "problem drinking" discordant pairs, were selected on the basis of either being5 discordant for the research criteria for alcoholism, which are composed of alcohol-related social problems and some medical criteria, on being discordant on the basis of an intrapair difference for average daily alcohol consumption of more than 8 cl pure alcohol. None of the problem drinking twins had ever had alcoholism of the severity of the WHO alcohol dependence syndrome. Some pairs were obtained from colleagues and some from the Institute of Psychiatry normal twin register. Twin pairs with widely discrepant birth weights indicating transfusion syndrome, and those with evidence of severe birth trauma were excluded.
diagnostic
CT Scan
Technique
Twins were examined with an EMI 1010 scanner. In half of the twin pairs both members were scanned at one session. In the remainder the interval between scans ranged from a few days to 3 months. Assessment of ventricular areas and volumes was done by M. A. R., who was blind to drinking history and to twin identity.
987 The use of our semi-automated method described below avoids the uncertainty of ventricular area measurements made with mechanical planimetry applied to X-ray films, as used in previous studies. CT scans were stored on randomly coded floppy discs which were then viewed on an independent viewing console. A light pen was used to draw a region of interest well around the ventricular space excluding the cisterns, on each tomographic slice on which the ventricles were seen. The computer then counted all those pixels within the density range of 0-25 Hounsfield units (HU) and summed them to give the ventricular area for each slice. The ventricular areas of all contiguous slices 1 cm thick were summed to give ventricular volume. Brain volume was calculated in the same way, with a range of0 to 99 HU being used as threshold, and it was in fact a measure of intracranial volume rather than actual brain volume. In the rest of this text the term "brain volume" is used to refer to intracranial volume. Ventricular brain ratio (VBR) was calculated from the area of the lateral ventricles divided by the brain area on that slice, and multiplied by 100.
Drinking History This was ascertained with the clinical alcohol interview schedule7 and the schizophrenia and affective disorders schedule, lifetime version (SADS-L), which yields the research diagnostic criteria (RDC).5 Drinking variables that were calculated from the two interviews included the following: number of years of "problem" drinking; number of years drinking 8 cl pure alcohol a day; number of years drinking 16 cl pure alcohol a day; peak alcohol consumption in centilitres per day; total life-time consumption in litres of pure alcohol; number of days abstinent before scan; longest continuous drinking episode in months; and number of weeks abstinent in previous year. The variable number of years of "problem" drinking was defined as the time a subject said his or her drinking had been a problem. In addition the twins were asked specifically about past episodes of amnesia. A special twin questionnaire provided items on birth order, birth weight, birth complications, pregnancy complications, developmental milestones, head injury, and laterality. Twins who were discordant for problems at birth or in childhood were excluded. Birth order as a possible cause of cerebral abnormality was investigated in relation to the CT scan changes, as were the drinking history variables.
Results
Dependent alcoholics had greater total ventricular volume, total ventricular/brain ratio, and larger ventricular area than TABLE I-MONOZYGOTIC TWINS DISCORDANT FOR THE
TABLE II-INTRACLASS CORRELATIONS IN SEVERELY AND MILDLY DISCORDANT ALCOHOLIC TWINS
in intraclass correlations (lc) between WHO and RDC groups 15 p<0. 05, calculated after the method of Vogel and Motulsky.
All differences
significant
at
variance-Intrapair variance Interpair Interpair variance + Intrapair variance did their cotwins (table I). The largest ventricle/brain ratio was computed by choosing both the greatest brain area on any slice and the greatest ventricular area; it too was altered in the expected direction (p=0’003). All these results indicate enlargement of the ventricular system in alcoholics. Confirmation of the above findings came from a comparison of the intraclass correlations (Ic) for brain scan variables in severely discordant alcoholic twin pairs with those in normal drinking identical twins investigated in our unit on the same scanner. In normal monozygotic twins the intraclass correlation has been called "heritability" by Osborne and DeGeorge,’° it is an estimate of both between and within pair variance. A high intraclass correlation indicates less within-pair variance than between-pair variance and it is an index of a high degree of genetic determination for the trait in question. Normal monozygotic twins had intraclass correlations of 0’ 84 for total ventricular volume, 0’ 82 for ventricle/brain ratio, and 0’ 77 for largest ventricular area,6,9 but the values for our severely discordant pairs were lower (table II). The pairs discordant either for the RDC criteria or for problem drinking had intraclass correlations midway between normal twins and severely dependent alcoholics, and are not significantly different from normal twins. Among the mildly discordant pairs there was no tendency for increased ventricular size in the problem drinkers (table III). The normal cotwins of the severely dependent group had
ALCOHOL DEPENDENCE SYNDROME TABLE III-MONOZYGOTIC TWINS DISCORDANT FOR PROBLEM DRINKING (RDC CRITERIA) OR 8 Cl PURE ALCOHOL PER DAY
(MILDLY
*Results given
†<0.05.
as
mean±SD. *Results given
as
mean±SD.
DISCORDANT
PAIRS)
_
988 TABLE IV-PEARSONIAN CORRELATION COEFFICIENTS BETWEEN INTRAPAIR DRINKING DIFFERENCES AND INTRAPAIR BRAIN SCAN DIFFERENCES
*Correlations
significant
at
demonstrating that acute dehydration reduced, not increased, ventricular volume. We believe that our semimethod is an advance over the devices to measure ventricular size on photographic film used in other studies. One of these studies found ventricular enlargement in only 4 out of 37 severely dependent alcoholics,16 probably because it assessed ventricular change by the use of Evan’s ratio as measured on photographic film. Evan’s ratio, the ratio of maximum anterior horn width to the maximum inner skull width, is less sensitive to change than is a direct measure of ventricular volume. We could not establish statistically significant cerebral abnormalities in problem drinkers although we found that our mildly discordant pairs had intraclass correlations midway between the severely dicordant pairs and the normal monozygotic twins. The best predictor of ventricular enlargement was the length of time an alcoholic had drunk more than 8 cl pure alcohol a day or its equivalent (a bottle of wine or four doubles of spirits each day). We theorise that this level of consumption is probably the threshold at which drinking commonly becomes out of control, and this is reflected by the finding that alcoholics diagnosed by the WHO criteria as having the alcohol-dependence syndrome gave the longest histories of drinking at this level. Our results suggest that the Royal College of Psychiatrists were justified in warning individuals that drinking at the level of 8 cl pure alcohol daily may lead to severe dependence and subsequently to cerebral abnormalities. automated mechanical
p<0.05.
larger mean ventricular volume and mean area than did the cotwins of the less dependent alcoholics. This was further investigated by analysis of variance with age as a covariate because ventricular size increases with age. When the effect of age was removed in a covariance analysis (F ratio =2-85, significance ofF=0’107 for ventricular area) there was no significant difference between the two cotwin control groups. The same happened with total ventricular volume. Thus the increased ventricular size measures in the cotwins of severely dependent alcoholics could be explained by their older age or by factors that vary strongly with age; 6 pairs of the severely dependent twins were aged 50 or more, compared with only 2 in the mildly dependent group. Pearson product moment correlation coefficients between within-pair differences for each of the brain scan variables and within-pair differences for drinking-history variables (table IV) indicate that in the severely discordant group the number of years of drinking more than 8 cl pure alcohol a day correlated significantly with (a) total ventricular volume (r=0’55, p=0’039), (b) total ventricle/brain ratio (r=0-55, p 0’ 04), (c) largest ventricular area (r = 0 - 66, p 0’ 01), and (d) largest ventricle brain/ratio (r=0-65, p=001). None of the other correlations including number of days abstinent before scan were statistically significant. a
=
=
belief by
Discussion Our findings indicate significant ventricular enlargement in alcoholism which is not related simply to duration of abstinence. The possibility that such enlargement might be involved somehow in the causation of alcoholism rather than being a consequence of it has indirect support from the known association of personality disturbance with cerebral abnormalities;13 such personality disturbance might be a factor predisposing towards alcoholism. In addition, parents of alcoholics are often also alcoholic and cerebral abnormalities might arise in their offspring by an in-utero effect of alcohol.14 However, the absence of ventricular enlargement provides strong evidence that the cerebral abnormalities are secondary to rather than a cause of alcoholism. We believe that the cerebral abnormalities which have been reported in alcoholism2,8,11,12 are not simply due to dehydration. Mellanby and Reveleyl5have confirmed our
computerised
The work was funded by grants from the Bethlem Royal Hospital Research Fund and by the Wellcome Trust.
and
Maudsley
The Medical Research Council supported M. A. R. and provided the independent viewing console as part of a grant to Professor W. A. Lishman.
Correspondence should be addressed to H.
M. D. G.
REFERENCES 1. Ron MA. Brain damage in chronic alcoholism: a neuropathological, neuroradiological and psychological review. Psychol Med 1977; 7: 1013-112 2. Ron MA, Acker W, Shaw GK, Lishman WA. Computerised tomography of the brain in chronic alcoholism. A survey and follow up study. Brain 1982; 105: 497-514 3. Acker W. Objective psychological changes in alcoholics after the withdrawal of alcohol. Br Med Bull 1982, 38: 95-98. 4. Edwards G, Gross MM, Keller M, Moser J, Room R Alcohol related disabilities. WHO Offset Publ no 32, 1977. 5. Spitzer RL, Endicott J, Robins E Research diagnostic criteria for a selected group of functional disorders, 2nd ed. New York Biometrics Research Division, New York State Psychiatric Institute, 1975 6. Reveley MA. The measurement of cerebral ventricular volume a comparison of computerised and planimetric methods. Paper presented to the Royal College of Psychiatrists, London, November 1983. 7. Caetano R, Edwards G, Oppenheim AN, Taylor C. Building a standardised alcoholism interview schedule Drug Alc Dependence 1978; 3: 185-97. 8. Bergman H, Borg S, Hindmarsh T, Idestrom CM, Mutzell S. Computed tomography of the brain and neuropsychological assessment of male alcoholic patients and a random sample from the general male population. Acta Psychiatrica Scand 1980; 62 (suppl 286): 47-56. 9. Reveley AM, Reveley MA, Chitkara B, Clifford CA. Genetics of cerebral ventricular volume. Psychiatry Res (in press). 10. Osborne RH, DeGeorge FV. Genetic basis of morphological variation-an evaluation and application of the twin study method. Cambridge, Massachusetts Harvard University Press, 1959. 11. Cala LA, Jones B, Wiley B, Mastaglia FL. A computerised axial tomography study of alcohol induced cerebral atrophy; in conjunction with other correlates. Acta Psychiatrica Scand 1980; 62 (suppl 286): 31-40. 12. Carlen PL, Wilkinson DA. Alcoholic brain damage and reversible deficits. Acta Psychiatrica Scand 1980; 62 (suppl 286): 103-18. 13. Scott PD. Medical aspects of delinquency. In: Contemporary psychiatry-selected reviews from the British Journal of Hospital Medicine. Br J Psychiatry special publication no 9. London: Headley Bros. 14. Bohman M, Srgvardsson S, Cloninger RC. Maternal inheritance of alcohol abuse. Arch Gen Psychiatry 1981; 38: 965-69. 15. Mellanby AR, Reveley MA. Effects of acute dehydration on computerised tomographic assessment of cerebral density and ventricular volume. Lancet 1982; ii: 874 16. Lee K, Moller L, Hardt F, Haubek A, Jensen E. Alcohol-induced brain damage and liver damage in young males. Lancet 1979; ii: 759-61. 17. Vogel P, Motulsky AG. Human genetics. Berlin: Springer Verlag, 1982: 586-90.
INCREASED CEREBRAL VENTRICULAR VOLUME IN MONOZYGOTIC TWINS DISCORDANT FOR ALCOHOLISM
careful zinc monitoring should be applied to all patients who show low FTS activity. The possibility of dietary zinc supplementation should be investigated. The measurement of FTS activity by bioassay before and after addition of zinc salts to plasma samples could help in identifying those who might benefit from such
supplementation. This work, done within the framework of EURAGE, was supported by a grant from Consiglio Nazionale delle Ricerche CT81.00196.04 and by a grant from the Progetto Finalizzato Medicina Preventiva e RiabilitativaSottoprogetto Meccanismi di Invecchiamento to N. F., and by grants 8101371961 and 82.02174.56 to C. F., within the Progetto Finalizzato sul Controllo della Crescita Neoplastica-Sottoprogetto Controllo Immunologico and within the Progetto Finalizzato Medicina Preventiva e RiabilitativaSottoprogetto Meccanismi di Invecchiamento respectively. We thank Dr A. Bernardini and Dr M. Mariottini of Laboratorio di Igiene e Profilassi of Ancona for the zmc determination and Mrs Nazzarena Gasparini for her excellent technical assistance.
Correspondence should be addressed to N. F., Department, Via Birarelli 8, 60100 Ancona, Italy.
INRCA Research
REFERENCES
T, Kay Age influence on the immune system. Adv Immunol 1980; 29: 287-330. 2. Licastro F, Chiricolo M, Tabacchi P, Parente R, Cerici M, Barboni F, Franceschi C. Defective self recognition in subjects of far advanced age. Gerontology 1983; 29: 64-72. 3. Levin S, Schlesinger M, Handzel Z, Hahn T, Altman Y, Czenobisky B, Boss Y. Thymic deficiency in Down’s syndrome. Pediatrics 1979; 63: 80-84. 4. Walford RL, Naeim F, Hall KY, Tam CF, Gatti RA, Medici M. Accelerated aging in Down’s syndrome: the concept of heirarchical homeostasis in relation to local and global failure. In: Fabris N, Garaci E, Hadden J, Mitchison NA, eds. Immunoregulation. London: Plenum Press, 1983: 399-417. 5. Franceschi C, Licastro F, Paolucci P, Masi M, Cavicchi S, Zannotti M. T and B lymphocyte subpopulations in Down’s syndrome. A study on non-institutionalized subjects. J Ment Defic Res 1983; 22: 179-91. 6. Martin GM. Genetic and evolutionary aspects of aging. Fed Proc 1979; 38: 1962-67. 7. Singh V, Singh AK. Age-related changes in human thymus. Clin Exp Immunol 1979; 37: 507-17. 8. Fabris N, Pierpaoli P, Sorkin E. Lymphocytes, hormones and ageing. Nature 1972; 240: 557-59. 9. McClure JE, Goldstein AL. Changes with age in blood levels of thymosin &agr;1 as measured by radioimmunoassay. (Abstr). 4th International Congress of Immunology, Paris, 1980; 17:2.26. 10. Bach JF, Dardenne M, Papernik M, Barois A, Levasseur P, Le Brigand H. Evidence for a serum factor produced by the human thymus. Lancet 1972; ii: 1056-58. 11. Lewis VM, Twomey JJ, Beahmear P, Goldstein G, Good RA. Age, thymic involution and circulating thymic hormone activity. J Clin Endorcinrol Metab 1978; 47: 145-50. 12. Franceschi C, Licastro F, Chiricolo M, Bonetti E, Zannotti M, Fabris N, Mocchegiani E, Fantini MP, Paolucci P, Masi M. Deficiency of autologous mixed lymphocyte reactions and serum thymic factor level in Down’s syndrome. J Immunol 1981; 126: 2161-64. 13. Weksler ME, Innes JB, Goldstein G. Immunological studies of aging. IV. The contribution of thymic involution to the immune deficiencies of aging mice and reversal with thymopoietin. J Exp Med 1978; 148: 996-1006. 14. Savmo W, Dardenne M, Papiernik M, Bach JF. Thymic hormone-containing cells. Characterization and localization of serum thymic factor in young mouse thymus studied by monoclonal antibodies. J Exp Med 1982; 156: 628-33. 15. Oosterom R, Kater L. Human thymic epithelial conditioned medium; biological activity and its similarity to thymosin. In: Aiuti F, Wigzell H, eds. Thymus, thymic hormones and T lymphocytes. London: Academic Press, 1980: 245-55. 16. Bach JF. Thymic hormones, their role in T cell differentiation, regulation of immunity and aging. In: Proceedings of Vth International Congress of Immunology. NorthHolland: Excerpta Medica, (in press). 17. Editorial. Lancet 1983; i: 1309-11. 18. Bach MA, Beauram G. Respective influence of extrinsic and intrinsic factors on the age-related decrease of thymic secretion. J Immunol 1979; 122: 2505-07. 19. Dardenne M, Savino W, Gastinel LN, Nabama B, Bach JF. Thymic disfunction in the mutant diabetic (db/db) mouse J Immunol 1983; 130(3): 1195-99. 20. Dardenne M, Pleau JM, Nabama B, Lefancier P, Denien M, Choay J, Bach JF. Contribution of zinc and other metals to the biological activity of the serum thymic factor. Proc Natl Acad Sci USA 1982; 79: 5370-73. 21. Ohga K, Incefy GS, Fok KF, Erickson BW, Good RA. Radioimmunoassays of the 1. Makinodan
thymic hormone serum thymic factor (FTS). J Immunol Methods 1983; 57: 171-84. JM. Current knowledge on zinc, copper and chromium in aging. Wid Rev Nutr
24.
25.
Diet 1979, 33: 42-69. Bjorksten B, Back O, Gustavson KH, Hallmans G, Hagglof B, Tornvik A. Zinc and immune function in Down’s syndrome. Acta Pediatr Scand 1980; 69: 183-87. Fernandez FJ, Kahn HL. Clinical methods for atomic absorption spectroscopy. Clin Chemistry Newsletter 1971; 3: 24-28. Pleau JM, Dardenne M, Blanot D, Bricas E, Bach JF. Antagonist analogues of serum thymic factor (FTS) interacting with the FTS cellular receptor. Immunol Lettrs
1979; 1: 179-82. 26.
Genetics Section,
Department of Psychiatry, Institute of Psychiatry, University of London, De Crespigny Park, London SE5 8AF
pairs of monozygotic twins discordant for and heavy drinking were examined by computerised tomography. Brain and ventricular volumes were calculated by the use of a semiautomated method with the rater blind to twinship and drinking history. 11 severely dependent alcoholics had larger Summary
21
alcoholism
ventricular volumes and ventricle/brain ratios than did their normal cotwins. These changes correlated best with the length of time the alcoholic twin had been drinking eight centilitres pure alcohol, equivalent to a bottle of wine, a day.
MMB.
22. Hsu 23.
H. M. D. GURLING MICHAEL A. REVELEY R. M. MURRAY
Chandra RK, Dayton DH. Trace element regulating immunity and infection. Nutr Res 1982; 2: 721-33.
27. Fraker PS. Zinc deficiency: 1983; 2: 155-63
a common
immunodeficiency
state.
Surv Immunol Res
Introduction ALCOHOLISM has been found to cause enlarged ventricles and widened cortical sulci.1 The changes, which are partly reversible,2 correlate with the length of time an alcoholic has been abstinent before CT scanning.’ The abnormalities represent a reduction in the volume of brain substance and correlate to a variable extent with psychological deficits in abstract reasoning and tactual performance.3 The twin method offers the considerable advantage of controlling perfectly for genetic predisposition and age. We have examined whether the alcoholic or heavy drinking member of a discordant identical twin pair has detectable ventricular abnormality, and whether any change found is related to
dependence or merely to heavy drinking. Methods
Selection
of Patients
pairs of monozygotic twins discordant for drinking behaviour recruited from a variety of sources, mainly the Maudsley Hospital twin register, which yielded 11 pairs in which one member met the World Health Organisation criteria for the alcohol dependence syndromes4—namely, increased tolerance to alcohol; repeated withdrawal symptoms; repeated relief or avoidance of withdrawal symptoms by further drinking; subjective awareness of a compulsion to drink; and reinstatement of the syndrome after 21
were
abstinence. The second group of 10 pairs of twins, known as the "problem drinking" discordant pairs, were selected on the basis of either being5 discordant for the research criteria for alcoholism, which are composed of alcohol-related social problems and some medical criteria, on being discordant on the basis of an intrapair difference for average daily alcohol consumption of more than 8 cl pure alcohol. None of the problem drinking twins had ever had alcoholism of the severity of the WHO alcohol dependence syndrome. Some pairs were obtained from colleagues and some from the Institute of Psychiatry normal twin register. Twin pairs with widely discrepant birth weights indicating transfusion syndrome, and those with evidence of severe birth trauma were excluded.
diagnostic
CT Scan
Technique
Twins were examined with an EMI 1010 scanner. In half of the twin pairs both members were scanned at one session. In the remainder the interval between scans ranged from a few days to 3 months. Assessment of ventricular areas and volumes was done by M. A. R., who was blind to drinking history and to twin identity.
987 The use of our semi-automated method described below avoids the uncertainty of ventricular area measurements made with mechanical planimetry applied to X-ray films, as used in previous studies. CT scans were stored on randomly coded floppy discs which were then viewed on an independent viewing console. A light pen was used to draw a region of interest well around the ventricular space excluding the cisterns, on each tomographic slice on which the ventricles were seen. The computer then counted all those pixels within the density range of 0-25 Hounsfield units (HU) and summed them to give the ventricular area for each slice. The ventricular areas of all contiguous slices 1 cm thick were summed to give ventricular volume. Brain volume was calculated in the same way, with a range of0 to 99 HU being used as threshold, and it was in fact a measure of intracranial volume rather than actual brain volume. In the rest of this text the term "brain volume" is used to refer to intracranial volume. Ventricular brain ratio (VBR) was calculated from the area of the lateral ventricles divided by the brain area on that slice, and multiplied by 100.
Drinking History This was ascertained with the clinical alcohol interview schedule7 and the schizophrenia and affective disorders schedule, lifetime version (SADS-L), which yields the research diagnostic criteria (RDC).5 Drinking variables that were calculated from the two interviews included the following: number of years of "problem" drinking; number of years drinking 8 cl pure alcohol a day; number of years drinking 16 cl pure alcohol a day; peak alcohol consumption in centilitres per day; total life-time consumption in litres of pure alcohol; number of days abstinent before scan; longest continuous drinking episode in months; and number of weeks abstinent in previous year. The variable number of years of "problem" drinking was defined as the time a subject said his or her drinking had been a problem. In addition the twins were asked specifically about past episodes of amnesia. A special twin questionnaire provided items on birth order, birth weight, birth complications, pregnancy complications, developmental milestones, head injury, and laterality. Twins who were discordant for problems at birth or in childhood were excluded. Birth order as a possible cause of cerebral abnormality was investigated in relation to the CT scan changes, as were the drinking history variables.
Results
Dependent alcoholics had greater total ventricular volume, total ventricular/brain ratio, and larger ventricular area than TABLE I-MONOZYGOTIC TWINS DISCORDANT FOR THE
TABLE II-INTRACLASS CORRELATIONS IN SEVERELY AND MILDLY DISCORDANT ALCOHOLIC TWINS
in intraclass correlations (lc) between WHO and RDC groups 15 p<0. 05, calculated after the method of Vogel and Motulsky.
All differences
significant
at
variance-Intrapair variance Interpair Interpair variance + Intrapair variance did their cotwins (table I). The largest ventricle/brain ratio was computed by choosing both the greatest brain area on any slice and the greatest ventricular area; it too was altered in the expected direction (p=0’003). All these results indicate enlargement of the ventricular system in alcoholics. Confirmation of the above findings came from a comparison of the intraclass correlations (Ic) for brain scan variables in severely discordant alcoholic twin pairs with those in normal drinking identical twins investigated in our unit on the same scanner. In normal monozygotic twins the intraclass correlation has been called "heritability" by Osborne and DeGeorge,’° it is an estimate of both between and within pair variance. A high intraclass correlation indicates less within-pair variance than between-pair variance and it is an index of a high degree of genetic determination for the trait in question. Normal monozygotic twins had intraclass correlations of 0’ 84 for total ventricular volume, 0’ 82 for ventricle/brain ratio, and 0’ 77 for largest ventricular area,6,9 but the values for our severely discordant pairs were lower (table II). The pairs discordant either for the RDC criteria or for problem drinking had intraclass correlations midway between normal twins and severely dependent alcoholics, and are not significantly different from normal twins. Among the mildly discordant pairs there was no tendency for increased ventricular size in the problem drinkers (table III). The normal cotwins of the severely dependent group had
ALCOHOL DEPENDENCE SYNDROME TABLE III-MONOZYGOTIC TWINS DISCORDANT FOR PROBLEM DRINKING (RDC CRITERIA) OR 8 Cl PURE ALCOHOL PER DAY
(MILDLY
*Results given
†<0.05.
as
mean±SD. *Results given
as
mean±SD.
DISCORDANT
PAIRS)
_
988 TABLE IV-PEARSONIAN CORRELATION COEFFICIENTS BETWEEN INTRAPAIR DRINKING DIFFERENCES AND INTRAPAIR BRAIN SCAN DIFFERENCES
*Correlations
significant
at
demonstrating that acute dehydration reduced, not increased, ventricular volume. We believe that our semimethod is an advance over the devices to measure ventricular size on photographic film used in other studies. One of these studies found ventricular enlargement in only 4 out of 37 severely dependent alcoholics,16 probably because it assessed ventricular change by the use of Evan’s ratio as measured on photographic film. Evan’s ratio, the ratio of maximum anterior horn width to the maximum inner skull width, is less sensitive to change than is a direct measure of ventricular volume. We could not establish statistically significant cerebral abnormalities in problem drinkers although we found that our mildly discordant pairs had intraclass correlations midway between the severely dicordant pairs and the normal monozygotic twins. The best predictor of ventricular enlargement was the length of time an alcoholic had drunk more than 8 cl pure alcohol a day or its equivalent (a bottle of wine or four doubles of spirits each day). We theorise that this level of consumption is probably the threshold at which drinking commonly becomes out of control, and this is reflected by the finding that alcoholics diagnosed by the WHO criteria as having the alcohol-dependence syndrome gave the longest histories of drinking at this level. Our results suggest that the Royal College of Psychiatrists were justified in warning individuals that drinking at the level of 8 cl pure alcohol daily may lead to severe dependence and subsequently to cerebral abnormalities. automated mechanical
p<0.05.
larger mean ventricular volume and mean area than did the cotwins of the less dependent alcoholics. This was further investigated by analysis of variance with age as a covariate because ventricular size increases with age. When the effect of age was removed in a covariance analysis (F ratio =2-85, significance ofF=0’107 for ventricular area) there was no significant difference between the two cotwin control groups. The same happened with total ventricular volume. Thus the increased ventricular size measures in the cotwins of severely dependent alcoholics could be explained by their older age or by factors that vary strongly with age; 6 pairs of the severely dependent twins were aged 50 or more, compared with only 2 in the mildly dependent group. Pearson product moment correlation coefficients between within-pair differences for each of the brain scan variables and within-pair differences for drinking-history variables (table IV) indicate that in the severely discordant group the number of years of drinking more than 8 cl pure alcohol a day correlated significantly with (a) total ventricular volume (r=0’55, p=0’039), (b) total ventricle/brain ratio (r=0-55, p 0’ 04), (c) largest ventricular area (r = 0 - 66, p 0’ 01), and (d) largest ventricle brain/ratio (r=0-65, p=001). None of the other correlations including number of days abstinent before scan were statistically significant. a
=
=
belief by
Discussion Our findings indicate significant ventricular enlargement in alcoholism which is not related simply to duration of abstinence. The possibility that such enlargement might be involved somehow in the causation of alcoholism rather than being a consequence of it has indirect support from the known association of personality disturbance with cerebral abnormalities;13 such personality disturbance might be a factor predisposing towards alcoholism. In addition, parents of alcoholics are often also alcoholic and cerebral abnormalities might arise in their offspring by an in-utero effect of alcohol.14 However, the absence of ventricular enlargement provides strong evidence that the cerebral abnormalities are secondary to rather than a cause of alcoholism. We believe that the cerebral abnormalities which have been reported in alcoholism2,8,11,12 are not simply due to dehydration. Mellanby and Reveleyl5have confirmed our
computerised
The work was funded by grants from the Bethlem Royal Hospital Research Fund and by the Wellcome Trust.
and
Maudsley
The Medical Research Council supported M. A. R. and provided the independent viewing console as part of a grant to Professor W. A. Lishman.
Correspondence should be addressed to H.
M. D. G.
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