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NORMAL AGEING, IMPAIRED COGNITIVE FUNCTION, AND SENILE DEMENTIA OF THE ALZHEIMER'S TYPE: A CONTINUUM?
1265
Dogma Disputed NORMAL AGEING, IMPAIRED COGNITIVE FUNCTION, AND SENILE DEMENTIA OF THE ALZHEIMER’S TYPE: A CONTINUUM?
CAROL BRAYNE1
PAUL CALLOWAY2
1Department of Community Medicine, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, and 2Fulbourn Hospital, Cambridge There is little evidence to support the view that senile dementia of the Alzheimer’s type is distinct from the normal ageing process. The (SDAT) changes in brain function found in normal ageing, benign senescent forgetfulness, and SDAT can be seen as a continuum, which may reflect a single underlying process. The failure to account for this possibility in research design may explain why few risk factors for SDAT have been identified.
Summary
INTRODUCTION
THE prevalence of dementia rises steeply with agel and affects about 20% of people aged over 80.2 Senile dementia of the Alzheimer’s type (SDAT) is considered to be the most common type of dementia occurring in the UK.3 The pathognomonic changes associated with the diagnosis of SDAT are senile plaques and neurofibrillary tangles,44 though there is debate about the exact nature of these lesions.5,6 The changes are also found in "normal" aged brains, although in smaller numbers.7 BrodyS suggested that "neuropathological changes associated with Alzheimer’s disease appear so frequently among the elderly as to raise the question whether SDAT is a disease or part of normal ageing". In an unselected necropsy series, Miller et al9 found that the number of plaques and tangles in brain sections including the hippocampal gyri was positively correlated with age in subjects aged over 71. It has been suggested that dementia appears only when the number of plaques and tangles in the brain reaches a critical level. 10 This view is implicit in the guidelines for the pathological diagnosis of SDAT suggested by the Medical Research Council Working Group on Alzheimer’s disease." However, not all subjects with a pathological diagnosis of SDAT have manifested dementia during life.12 Differences between normal subjects and patients with SDAT have been reported for a variety of neurotransmitter systems, particularly the cholinergic system." Differences have also been revealed in many other systems, although, when compared with the changes found in non-demented old people, the differences appear to be quantitative, not qualitative.l4 Indeed, SDAT research has been likened to
38. Black
39
MM, Nishiaka K, Levene GM The role of dermal blood vessels m the pathogenesis of malignant atrophic papulosis (Degos’ disease): a study of two cases using enzyme, histochemical, fibrinolytic, electronmicroscopical and immunological techniques. Br J Dermatol 1973, 88: 213-18 Roenigk HH, Farmer RG. Degos’ disease (malignant papulosis). JAMA 1968; 206:
1508-14 40. Pizzo SV, Murray JC, Gonias SL. Atrophie blanche. A disorder associated with defective release of ussue plasminogen activator. Arch Pathol Lab Med 1986, 110: 517-20.
41
Mayou SC, Asherson RA, Black MM, Cooke DAP, Hughes GRV Livedo reticularis, anticardiolipin antibodies, CNS complications and tissue plasminogen. Br J Dermatol 1988; 118: 300
the fable of the blind men examining an elephant, in that each aspect examined renders a new finding without necessarily leading to any greater understanding of the whole.15 There have been few clinicopathological studies because of the difficulties of obtaining brains for necropsy from subjects studied during life. Blessed et al 16 found a significant correlation between scales based on cognitive function and behavioural changes (asked of an informant) and senile plaques. Perry et al’ found a significant correlation between these scales and levels of choline acetyltransferase. These scales were relatively crude, and the subjects were hospital-based. Other studies have reported similar findings, although not all have found significant correlations. 18,19 Risk factors for SDAT have been sought by means of case-control studies and family studies .20 The risk factors that have been identified by more than one study include age, family history of SDAT, head injury, Down’s syndrome, and family history of Down’s syndrome. However, Down’s syndrome subjects show premature ageing, as well as Alzheimer changes in the brain at a young age.21 Genetic studies have suggested that SDAT may be due to a single autosomal dominant gene with expression late in life.22 If so, the gene might be present in at least 20% of the population, since this proportion of people aged over 80 are said to have dementia.1 Indeed, it might be argued that the gene is universal but that its expression is modified by other factors, environmental and genetic. Some authors suggest that there are two distinct forms of Alzheimer’s disease, a presenile and a senile form.23 The younger group tend to be more severely affected, with more neuropathological and neurochemical abnormalities. However, this pattern is also seen in other diseases, such as ischaemic heart disease and breast cancer. The younger patients often have more risk factors, particularly family history-it is not argued that the disorder itself is different. As research into SDAT has concentrated more on searching for a fundamental lesion, there has been less debate about the relevance of these findings to the community. Bimodal distributions of variables measured before and after death have often been interpreted as confirming that SDAT is qualitatively different from normal ageing.24.25 However, most of these studies have been done on highly selected groups which are not representative of the community. Under these conditions bimodality would not necessarily exclude an underlying unimodal distribution.26.27 Despite significant differences between indicators of SDAT in "normal" and affected subjects, overlap has been noted between the groups in both biological and psychometric studies.28.29 It has been suggested that a dimensional approach to the study of SDAT and ageing would be more appropriate than a categorical one,8,30 but few studies have attempted this, partly because of the lack of a biological marker for the diagnosis of SDAT. We argue here that such a biological marker, if one exists, would be unimodally distributed in a community sample, and any individual’s position on the continuum would depend on a number of risk factors, of which only a few have been identified so far. Since no biological marker is known, evidence of bimodality can be sought in the distribution of variables associated with SDAT. The distribution of plaques and tangles cannot be examined in a truly representative community sample, but it is possible to examine the
1266
Venepuncture was also done for routine haematological and biochemical analysis, thyroid function tests, autoantibodies, and creatine kinase isoenzymes. The interviews were conducted by one of the authors (C. B.) in the subjects’ homes. They were carried out in the 12 months following October, 1985. 365 women (89-0%) of the total sample agreed to take part in the study. Of the remaining 45, 10 died before being approached and 35 refused. All but 4 of these 35 were seen by C. B. In terms of the diagnosis of dementia those who refused appeared to be different from the responders. An informant was also interviewed for 95-6% of the responders. The frequency distributions for the cognitive function (information-memory scale) and behaviour (Blessed dementia scale) scores were highly skewed, unimodal, and smooth (figs 1 and 2). The distributions on more detailed cognitive scales (not shown) were similar but attenuated, with weaker ceiling and floor effects, and resembled the shape of most physiological variables. All the scales measured in this community sample showed the same shape of distribution. The correlation between the information-memory cognitive scale and the Blessed dementia scale was significant and was stronger in the older age group than the younger (r= -0-009, not significant, for the 70-74 age group; r = - 0-26, p < 0-001, for the 75-79 age group). This difference may reflect the higher frequency of neuropathological lesions in the older group.
no
Fig 1-Distribution of scores on the information-memory scale. distribution of the information-memory scale and Blessed dementia scale scores, which have been shown to correlate with the presence of plaques and tangles, and also with the degree of cholinergic deficit.16.17 THE STUDY
410 women aged 70 to 79 from a single health centre in rural Cambridgeshire were sampled including those in institutions, so that the full range of possible function was represented. This was made up of a 75% random sample of the 70-74 age group and all those in the 75-79 age group. The interview consisted of CAMDEX (Cambridge Mental
Disorders of the Elderly Examination),31 a standardised psychiatric interview designed for the detection of early dementia in the elderly. It contains many established scales used in the investigation of dementia, including a modified version of the Blessed dementia scale and the information memory concentration scale used by Blessed et al and Perry et al in clinicopathological studies.16,17 Additional questions were added, and the full interview covered all areas suggested by the MRC Working Group on Alzheimer’s Disease;" basic demographic data about the subject, history from an informant, comprehensive cognitive assessment (including mini mental state examination12), psychiatric assessment of mental state, and physical examination.
DISCUSSION
These
findings indicate that in a truly representative community sample there is a continuous distribution of at least
of the manifest variables associated with SDAT. until a valid biological marker is found for SDAT, However, some
only a sample
necropsy
study
on
a
representative community
could confirm this distribution. Cognitive and behavioural changes are associated with ageing,33 and Jenkyn et a134 found that the frequency of abnormal neurological signs rose with age, particularly over age 70. In the community, "normal" ageing, benign senescent forgetfulness,35 and SDAT do not fall into discrete categories but appear to lie on a continuum. Although these groupings are useful for planning treatment, the cut-off points are arbitrary. The model of a continuum is consistent with the suggestion that normal ageing could be viewed as either "successful" or "usual".36 In terms of brain function, the "successful" group would have few if any of the lesions associated with SDAT, whereas the "usual" group would be in the intermediate range. Similar issues were raised by Pickering in the 1950s.37 Future research should combine biological and epidemiological approaches, moving away from the model of "has he got it?" to that of "how much of it has he got?"38 and "why?". This study was done while C. B. was a Medical Research Council traming fellow in epidemiology, and was supported by the Mental Health Foundation. We thank Dr Felicia Huppert, Prof Roy Acheson, Sir Martin Roth, Prof Anthony Mann, Prof Gerry Shaper, the general practitioners, the health-centre staff and the subjects who took part in the study.
Correspondence should be addressed to C. B. REFERENCES 1 Pfeffer
RI, Afifi AA, Chance JM Prevalence of Alzheimer’s disease
community
Fig 2-Distribution of scores on the Blessed dementia scale.
Am JEpidemiol 1987,
125: 420-36
in a retirement
1267
Before Our Time RHEUMATIC DISEASE, HEAVY-METAL PIGMENTS, AND THE GREAT MASTERS LISBET MILLING PEDERSEN
HENRIK PERMIN
Departments of Infectious Diseases, Rigshospitalet and Medical Department F, KAS-Gentofte, University Hospitals, Copenhagen, Denmark
The painters Rubens, Renoir, and Dufy suffered from rheumatoid arthritis and Klee from scleroderma. Analysis of the areas of various colours in randomly selected paintings by these four artists and by eight "controls" (contemporary painters without rheumatic disease) suggests that Rubens, Renoir, Dufy, and Klee used significantly more bright and clear colours based on toxic heavy metals and fewer earth colours containing harmless iron and carbon compounds. These four painters may have been heavily exposed to mercury sulphide, cadmium sulphide, arsenic sulphide, lead, antimony, tin, cobalt, manganese, and chromium, the metals of the bright and clear colours, and exposure to these metals may be of importance in the development of inflammatory rheumatic diseases. Artists today are not so exposed, but heavy metal contamination in food and drinking water exists and experience from the occupational exposure of old masters is still relevant.
Summary
INTRODUCTION
THE causes of inflammatory rheumatic disease are almost certainly multifactorial but environmental factors may act as
Kay DWK, Beamish P, Roth M. Old age mental disorders in Newcastle upon Tyne. I. A study of prevalence. Br J Psychiatry 1964; 110: 116-58. 3. Royal College of Physicians, Committee on Geriatrics. Organic mental impairment in the elderly; implications for research, education and the provision of services. J R Coll Physns Lond 1981; 15: 141-67. 4. Tomlinson BE, Blessed G, Roth M Observations on the brains of demented old people. J Neurol Sci 1970; 11: 205-42. 5. Iqbal K, Grundke-Iqbal I, Zaidi T, et al. Defective brain microtubule assembly in 2.
Alzheimer’s disease. Lancet 1986; ii: 421-26. 6. Editorial Alzheimer’s disease, Down’s syndrome, and chromosome 21 Lancet 1987; i: 1011-12. 7. Tomlinson BE, Blessed G, Roth M. Observations on the brains of non-demented old people. J Neurol Sci 1968; 7: 331-56. 8. Brody JA. An epidemiologist views senile dementia-facts and fragments. Am J Epidemiol 1982, 115: 155-62. 9. Miller FD, Hicks SP, D’Amato CJ, Landis JR. A descriptive study of neuritic plaques and neurofibnllary tangles in an autopsy population Am J Epidemiol 1984; 3: 331-41 10. Roth M, Tomlinson BE, Blessed G. Correlation between scales for dementia and counts of "senile plaques" in cerebral grey matter of elderly subjects. Nature 1966; 209: 109. 11. Medical Research Council Working Group on Alzheimer’s Disease. Conclusions from workshop, September, 1987. 12. Newton RD. The identity of Alzheimer’s disease and senile dementia and their relationship to senility. J Ment Sci 1948; 94: 225-49 13. Katzman R, Brown T, Fuld P, Thal L, Davies P, Terry R. Significance of neurotransmitter abnormalities in Alzheimer’s disease. Res Publ Ass Res Nerv Ment Dis 1986; 64: 279-86. 14. Whitehouse PJ. Understanding the aetiology of Alzheimer’s disease: Current approaches. Neurol Clin 1986; 17: 278-82. 15. Wurtman RJ. Alzheimer’s disease. Sci Am 1985; 252: 48-56. 16. Blessed G, Tomlinson BE, Roth M. The associaton between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J
Psychiatry 1968; 114: 797-811. 17. Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J 1978; ii: 1457-59. 18 Neary D, Snowden JS, Mann DM, et al. Alzteimer’s disease: A correlative study. J Neurol Neurosurg Psychiat 1986, 49: 229-37. 19. Wilcock GK, Esin MM. Plaques, tangles and dementia: A quantitative study. J Neurol Sci 1982; 56: 343-56.
triggers in people predisposed to these illnesses. Evidence from paintings and literature suggest that rheumatoid arthritis was rare before the 17th century. Peter Paul Rubens (1577-1640) seems to be one of the first cases to be described. Pierre Auguste Renoir (1841-1919) and Raoul Dufy (1877-1953) had advanced rheumatoid arthritis,12 while Paul Klee (1879-1940) had progressive systemic sclerosis (scleroderma).1 Could the occupations of these four men have been important to the development of their inflammatory rheumatic diseases? Artists can be heavily exposed to paint pigments and other harmful substances. A painter’s palette has several metal compounds (except black, which contains only carbon). Earth colours, such as yellow and red ochre, madder red, olive green, and brown, consist of harmless iron compounds. Olive green and madder red also contain non-toxic amounts of silicon and aluminium.3,4 On the other hand, bright and clear yellow, red, white, green, blue, and violet contain very toxic metals such as mercury, cadmium, arsenic, lead, antimony, chromium, tin, copper, cobalt, and manganese. 3,4
Artists’ colours consist of linseed oil, small amounts of aluminium stearate, and up to 80% pigment. As far back as 8000 BC Egyptians used cinnabar (mercury sulphide), brilliant blues and greens (organic copper), bright yellows (arsenic sulphide), red, yellow, and brown ochre (iron compounds), and madder red (plant extract).3,4 In the time between the Roman Empire and the Renaissance new colours were added: white lead carbonate, yellow lead oxide, antimonate, and stannate, and blue aluminium sulphosilicates and barium manganate. During the 19th century even more pigments based on heavy metals were adopted: blue cobalt aluminate, yellows (cadmium sulphide and chromium oxide), red cadmium sulphide, green chromium oxide, and violets (cobalt arsenate and manganese ammonium phosphate). WA, Amaducci LA, Schoenberg BS. Epidemiology of clinically diagnosed Alzheimer’s disease. Ann Neurol 1986; 19: 415-24. 21. Wismewski KE, Wisniewski HM, Wen GY. Occurrence of neuropathological changes and dementia of Alzheimers type in Down’s syndrome. Ann Neurol 1985, 17: 278-82. 22. Mohs RC, Breimer JCS, Silverman JM, Davis KL. Alzheimer’s disease: Morbid nsk among first degree relatives approximates 50% by 90 years of age. Arch Gen Psych 20. Rocca
1987; 44: 405-08. 23. Bondareff W Age and Alzheimer’s disease. Lancet 1983; i 1147. 24. Berg L. Does Alzheimer’s disease represent an exaggeration of normal aging? Arch Neurol 1985; 42: 737-39. 25. Creasey H, Rapoport SI. The aging human brain. Ann Neurol 1985; 17: 2-10 26. Everitt BS. Bimodality and the nature of depression Br J Psychiatry 1981; 138: 336-39. 27 Jorm AF. Subtypes of Alzheimer’s dementia: A conceptual analysis and critical review Psychol Med 1985, 15: 543-53. 28. Tamminga CA, Foster NL, Fedio P, Bird ED, Chase TN. Alzheimer’s disease—low somatostatin levels correlate with impaired cognitive function and cortical metabolism. Neurology, Minneap 1987, 37: 161-65 29. Little A, Hemsley D, Volans J Comparison of current levels of performance and scores based on change as diagnostic discriminators among the elderly Br J Clin
Psychol 1987; 26: 135-40. 30. Henderson AS. The epidemiology of Alzheimer’s disease. Br Med Bull 1986; 42: 3-10 31. Roth M, Tym E, Mountjow CQ, et al. CAMDEX- A standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia. Br JPsychiatry 1986; 149: 698-709 32. Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A practical method for grading the cognitive state of patients for the clinician J Psychiat Res 1975; 12: 189-98. 33 Schaie KW. In. Schaie KW, ed Longitudinal studies of adult psychological development. New York: Guildford Press, 1983 34. Jenkyn LR, Reeves AG, Warren T, et al. Neurologic signs in senescence Arch Neurol
1985, 42: 1154-57 Benign senescent forgetfulness In: Katzman R, Terry RD, Bicks KL, eds Aging, vol 7. Alzheimer’s disease: Senile dementia and related disorders. New York: Raven Press, 1978 36. Rowe JW, Kahn RL. Human aging: Usual and successful. Science 1987; 237: 143-49. 37 Pickering GW High blood pressure. New York Raven Press, 1955. 38. Barker DJP, Rose G. Epidemiology in medical practice Edinburgh- Churchill Livingstone, 1984 35. Kral VA.
Dogma Disputed NORMAL AGEING, IMPAIRED COGNITIVE FUNCTION, AND SENILE DEMENTIA OF THE ALZHEIMER’S TYPE: A CONTINUUM?
CAROL BRAYNE1
PAUL CALLOWAY2
1Department of Community Medicine, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, and 2Fulbourn Hospital, Cambridge There is little evidence to support the view that senile dementia of the Alzheimer’s type is distinct from the normal ageing process. The (SDAT) changes in brain function found in normal ageing, benign senescent forgetfulness, and SDAT can be seen as a continuum, which may reflect a single underlying process. The failure to account for this possibility in research design may explain why few risk factors for SDAT have been identified.
Summary
INTRODUCTION
THE prevalence of dementia rises steeply with agel and affects about 20% of people aged over 80.2 Senile dementia of the Alzheimer’s type (SDAT) is considered to be the most common type of dementia occurring in the UK.3 The pathognomonic changes associated with the diagnosis of SDAT are senile plaques and neurofibrillary tangles,44 though there is debate about the exact nature of these lesions.5,6 The changes are also found in "normal" aged brains, although in smaller numbers.7 BrodyS suggested that "neuropathological changes associated with Alzheimer’s disease appear so frequently among the elderly as to raise the question whether SDAT is a disease or part of normal ageing". In an unselected necropsy series, Miller et al9 found that the number of plaques and tangles in brain sections including the hippocampal gyri was positively correlated with age in subjects aged over 71. It has been suggested that dementia appears only when the number of plaques and tangles in the brain reaches a critical level. 10 This view is implicit in the guidelines for the pathological diagnosis of SDAT suggested by the Medical Research Council Working Group on Alzheimer’s disease." However, not all subjects with a pathological diagnosis of SDAT have manifested dementia during life.12 Differences between normal subjects and patients with SDAT have been reported for a variety of neurotransmitter systems, particularly the cholinergic system." Differences have also been revealed in many other systems, although, when compared with the changes found in non-demented old people, the differences appear to be quantitative, not qualitative.l4 Indeed, SDAT research has been likened to
38. Black
39
MM, Nishiaka K, Levene GM The role of dermal blood vessels m the pathogenesis of malignant atrophic papulosis (Degos’ disease): a study of two cases using enzyme, histochemical, fibrinolytic, electronmicroscopical and immunological techniques. Br J Dermatol 1973, 88: 213-18 Roenigk HH, Farmer RG. Degos’ disease (malignant papulosis). JAMA 1968; 206:
1508-14 40. Pizzo SV, Murray JC, Gonias SL. Atrophie blanche. A disorder associated with defective release of ussue plasminogen activator. Arch Pathol Lab Med 1986, 110: 517-20.
41
Mayou SC, Asherson RA, Black MM, Cooke DAP, Hughes GRV Livedo reticularis, anticardiolipin antibodies, CNS complications and tissue plasminogen. Br J Dermatol 1988; 118: 300
the fable of the blind men examining an elephant, in that each aspect examined renders a new finding without necessarily leading to any greater understanding of the whole.15 There have been few clinicopathological studies because of the difficulties of obtaining brains for necropsy from subjects studied during life. Blessed et al 16 found a significant correlation between scales based on cognitive function and behavioural changes (asked of an informant) and senile plaques. Perry et al’ found a significant correlation between these scales and levels of choline acetyltransferase. These scales were relatively crude, and the subjects were hospital-based. Other studies have reported similar findings, although not all have found significant correlations. 18,19 Risk factors for SDAT have been sought by means of case-control studies and family studies .20 The risk factors that have been identified by more than one study include age, family history of SDAT, head injury, Down’s syndrome, and family history of Down’s syndrome. However, Down’s syndrome subjects show premature ageing, as well as Alzheimer changes in the brain at a young age.21 Genetic studies have suggested that SDAT may be due to a single autosomal dominant gene with expression late in life.22 If so, the gene might be present in at least 20% of the population, since this proportion of people aged over 80 are said to have dementia.1 Indeed, it might be argued that the gene is universal but that its expression is modified by other factors, environmental and genetic. Some authors suggest that there are two distinct forms of Alzheimer’s disease, a presenile and a senile form.23 The younger group tend to be more severely affected, with more neuropathological and neurochemical abnormalities. However, this pattern is also seen in other diseases, such as ischaemic heart disease and breast cancer. The younger patients often have more risk factors, particularly family history-it is not argued that the disorder itself is different. As research into SDAT has concentrated more on searching for a fundamental lesion, there has been less debate about the relevance of these findings to the community. Bimodal distributions of variables measured before and after death have often been interpreted as confirming that SDAT is qualitatively different from normal ageing.24.25 However, most of these studies have been done on highly selected groups which are not representative of the community. Under these conditions bimodality would not necessarily exclude an underlying unimodal distribution.26.27 Despite significant differences between indicators of SDAT in "normal" and affected subjects, overlap has been noted between the groups in both biological and psychometric studies.28.29 It has been suggested that a dimensional approach to the study of SDAT and ageing would be more appropriate than a categorical one,8,30 but few studies have attempted this, partly because of the lack of a biological marker for the diagnosis of SDAT. We argue here that such a biological marker, if one exists, would be unimodally distributed in a community sample, and any individual’s position on the continuum would depend on a number of risk factors, of which only a few have been identified so far. Since no biological marker is known, evidence of bimodality can be sought in the distribution of variables associated with SDAT. The distribution of plaques and tangles cannot be examined in a truly representative community sample, but it is possible to examine the
1266
Venepuncture was also done for routine haematological and biochemical analysis, thyroid function tests, autoantibodies, and creatine kinase isoenzymes. The interviews were conducted by one of the authors (C. B.) in the subjects’ homes. They were carried out in the 12 months following October, 1985. 365 women (89-0%) of the total sample agreed to take part in the study. Of the remaining 45, 10 died before being approached and 35 refused. All but 4 of these 35 were seen by C. B. In terms of the diagnosis of dementia those who refused appeared to be different from the responders. An informant was also interviewed for 95-6% of the responders. The frequency distributions for the cognitive function (information-memory scale) and behaviour (Blessed dementia scale) scores were highly skewed, unimodal, and smooth (figs 1 and 2). The distributions on more detailed cognitive scales (not shown) were similar but attenuated, with weaker ceiling and floor effects, and resembled the shape of most physiological variables. All the scales measured in this community sample showed the same shape of distribution. The correlation between the information-memory cognitive scale and the Blessed dementia scale was significant and was stronger in the older age group than the younger (r= -0-009, not significant, for the 70-74 age group; r = - 0-26, p < 0-001, for the 75-79 age group). This difference may reflect the higher frequency of neuropathological lesions in the older group.
no
Fig 1-Distribution of scores on the information-memory scale. distribution of the information-memory scale and Blessed dementia scale scores, which have been shown to correlate with the presence of plaques and tangles, and also with the degree of cholinergic deficit.16.17 THE STUDY
410 women aged 70 to 79 from a single health centre in rural Cambridgeshire were sampled including those in institutions, so that the full range of possible function was represented. This was made up of a 75% random sample of the 70-74 age group and all those in the 75-79 age group. The interview consisted of CAMDEX (Cambridge Mental
Disorders of the Elderly Examination),31 a standardised psychiatric interview designed for the detection of early dementia in the elderly. It contains many established scales used in the investigation of dementia, including a modified version of the Blessed dementia scale and the information memory concentration scale used by Blessed et al and Perry et al in clinicopathological studies.16,17 Additional questions were added, and the full interview covered all areas suggested by the MRC Working Group on Alzheimer’s Disease;" basic demographic data about the subject, history from an informant, comprehensive cognitive assessment (including mini mental state examination12), psychiatric assessment of mental state, and physical examination.
DISCUSSION
These
findings indicate that in a truly representative community sample there is a continuous distribution of at least
of the manifest variables associated with SDAT. until a valid biological marker is found for SDAT, However, some
only a sample
necropsy
study
on
a
representative community
could confirm this distribution. Cognitive and behavioural changes are associated with ageing,33 and Jenkyn et a134 found that the frequency of abnormal neurological signs rose with age, particularly over age 70. In the community, "normal" ageing, benign senescent forgetfulness,35 and SDAT do not fall into discrete categories but appear to lie on a continuum. Although these groupings are useful for planning treatment, the cut-off points are arbitrary. The model of a continuum is consistent with the suggestion that normal ageing could be viewed as either "successful" or "usual".36 In terms of brain function, the "successful" group would have few if any of the lesions associated with SDAT, whereas the "usual" group would be in the intermediate range. Similar issues were raised by Pickering in the 1950s.37 Future research should combine biological and epidemiological approaches, moving away from the model of "has he got it?" to that of "how much of it has he got?"38 and "why?". This study was done while C. B. was a Medical Research Council traming fellow in epidemiology, and was supported by the Mental Health Foundation. We thank Dr Felicia Huppert, Prof Roy Acheson, Sir Martin Roth, Prof Anthony Mann, Prof Gerry Shaper, the general practitioners, the health-centre staff and the subjects who took part in the study.
Correspondence should be addressed to C. B. REFERENCES 1 Pfeffer
RI, Afifi AA, Chance JM Prevalence of Alzheimer’s disease
community
Fig 2-Distribution of scores on the Blessed dementia scale.
Am JEpidemiol 1987,
125: 420-36
in a retirement
1267
Before Our Time RHEUMATIC DISEASE, HEAVY-METAL PIGMENTS, AND THE GREAT MASTERS LISBET MILLING PEDERSEN
HENRIK PERMIN
Departments of Infectious Diseases, Rigshospitalet and Medical Department F, KAS-Gentofte, University Hospitals, Copenhagen, Denmark
The painters Rubens, Renoir, and Dufy suffered from rheumatoid arthritis and Klee from scleroderma. Analysis of the areas of various colours in randomly selected paintings by these four artists and by eight "controls" (contemporary painters without rheumatic disease) suggests that Rubens, Renoir, Dufy, and Klee used significantly more bright and clear colours based on toxic heavy metals and fewer earth colours containing harmless iron and carbon compounds. These four painters may have been heavily exposed to mercury sulphide, cadmium sulphide, arsenic sulphide, lead, antimony, tin, cobalt, manganese, and chromium, the metals of the bright and clear colours, and exposure to these metals may be of importance in the development of inflammatory rheumatic diseases. Artists today are not so exposed, but heavy metal contamination in food and drinking water exists and experience from the occupational exposure of old masters is still relevant.
Summary
INTRODUCTION
THE causes of inflammatory rheumatic disease are almost certainly multifactorial but environmental factors may act as
Kay DWK, Beamish P, Roth M. Old age mental disorders in Newcastle upon Tyne. I. A study of prevalence. Br J Psychiatry 1964; 110: 116-58. 3. Royal College of Physicians, Committee on Geriatrics. Organic mental impairment in the elderly; implications for research, education and the provision of services. J R Coll Physns Lond 1981; 15: 141-67. 4. Tomlinson BE, Blessed G, Roth M Observations on the brains of demented old people. J Neurol Sci 1970; 11: 205-42. 5. Iqbal K, Grundke-Iqbal I, Zaidi T, et al. Defective brain microtubule assembly in 2.
Alzheimer’s disease. Lancet 1986; ii: 421-26. 6. Editorial Alzheimer’s disease, Down’s syndrome, and chromosome 21 Lancet 1987; i: 1011-12. 7. Tomlinson BE, Blessed G, Roth M. Observations on the brains of non-demented old people. J Neurol Sci 1968; 7: 331-56. 8. Brody JA. An epidemiologist views senile dementia-facts and fragments. Am J Epidemiol 1982, 115: 155-62. 9. Miller FD, Hicks SP, D’Amato CJ, Landis JR. A descriptive study of neuritic plaques and neurofibnllary tangles in an autopsy population Am J Epidemiol 1984; 3: 331-41 10. Roth M, Tomlinson BE, Blessed G. Correlation between scales for dementia and counts of "senile plaques" in cerebral grey matter of elderly subjects. Nature 1966; 209: 109. 11. Medical Research Council Working Group on Alzheimer’s Disease. Conclusions from workshop, September, 1987. 12. Newton RD. The identity of Alzheimer’s disease and senile dementia and their relationship to senility. J Ment Sci 1948; 94: 225-49 13. Katzman R, Brown T, Fuld P, Thal L, Davies P, Terry R. Significance of neurotransmitter abnormalities in Alzheimer’s disease. Res Publ Ass Res Nerv Ment Dis 1986; 64: 279-86. 14. Whitehouse PJ. Understanding the aetiology of Alzheimer’s disease: Current approaches. Neurol Clin 1986; 17: 278-82. 15. Wurtman RJ. Alzheimer’s disease. Sci Am 1985; 252: 48-56. 16. Blessed G, Tomlinson BE, Roth M. The associaton between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J
Psychiatry 1968; 114: 797-811. 17. Perry EK, Tomlinson BE, Blessed G, Bergmann K, Gibson PH, Perry RH Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. Br Med J 1978; ii: 1457-59. 18 Neary D, Snowden JS, Mann DM, et al. Alzteimer’s disease: A correlative study. J Neurol Neurosurg Psychiat 1986, 49: 229-37. 19. Wilcock GK, Esin MM. Plaques, tangles and dementia: A quantitative study. J Neurol Sci 1982; 56: 343-56.
triggers in people predisposed to these illnesses. Evidence from paintings and literature suggest that rheumatoid arthritis was rare before the 17th century. Peter Paul Rubens (1577-1640) seems to be one of the first cases to be described. Pierre Auguste Renoir (1841-1919) and Raoul Dufy (1877-1953) had advanced rheumatoid arthritis,12 while Paul Klee (1879-1940) had progressive systemic sclerosis (scleroderma).1 Could the occupations of these four men have been important to the development of their inflammatory rheumatic diseases? Artists can be heavily exposed to paint pigments and other harmful substances. A painter’s palette has several metal compounds (except black, which contains only carbon). Earth colours, such as yellow and red ochre, madder red, olive green, and brown, consist of harmless iron compounds. Olive green and madder red also contain non-toxic amounts of silicon and aluminium.3,4 On the other hand, bright and clear yellow, red, white, green, blue, and violet contain very toxic metals such as mercury, cadmium, arsenic, lead, antimony, chromium, tin, copper, cobalt, and manganese. 3,4
Artists’ colours consist of linseed oil, small amounts of aluminium stearate, and up to 80% pigment. As far back as 8000 BC Egyptians used cinnabar (mercury sulphide), brilliant blues and greens (organic copper), bright yellows (arsenic sulphide), red, yellow, and brown ochre (iron compounds), and madder red (plant extract).3,4 In the time between the Roman Empire and the Renaissance new colours were added: white lead carbonate, yellow lead oxide, antimonate, and stannate, and blue aluminium sulphosilicates and barium manganate. During the 19th century even more pigments based on heavy metals were adopted: blue cobalt aluminate, yellows (cadmium sulphide and chromium oxide), red cadmium sulphide, green chromium oxide, and violets (cobalt arsenate and manganese ammonium phosphate). WA, Amaducci LA, Schoenberg BS. Epidemiology of clinically diagnosed Alzheimer’s disease. Ann Neurol 1986; 19: 415-24. 21. Wismewski KE, Wisniewski HM, Wen GY. Occurrence of neuropathological changes and dementia of Alzheimers type in Down’s syndrome. Ann Neurol 1985, 17: 278-82. 22. Mohs RC, Breimer JCS, Silverman JM, Davis KL. Alzheimer’s disease: Morbid nsk among first degree relatives approximates 50% by 90 years of age. Arch Gen Psych 20. Rocca
1987; 44: 405-08. 23. Bondareff W Age and Alzheimer’s disease. Lancet 1983; i 1147. 24. Berg L. Does Alzheimer’s disease represent an exaggeration of normal aging? Arch Neurol 1985; 42: 737-39. 25. Creasey H, Rapoport SI. The aging human brain. Ann Neurol 1985; 17: 2-10 26. Everitt BS. Bimodality and the nature of depression Br J Psychiatry 1981; 138: 336-39. 27 Jorm AF. Subtypes of Alzheimer’s dementia: A conceptual analysis and critical review Psychol Med 1985, 15: 543-53. 28. Tamminga CA, Foster NL, Fedio P, Bird ED, Chase TN. Alzheimer’s disease—low somatostatin levels correlate with impaired cognitive function and cortical metabolism. Neurology, Minneap 1987, 37: 161-65 29. Little A, Hemsley D, Volans J Comparison of current levels of performance and scores based on change as diagnostic discriminators among the elderly Br J Clin
Psychol 1987; 26: 135-40. 30. Henderson AS. The epidemiology of Alzheimer’s disease. Br Med Bull 1986; 42: 3-10 31. Roth M, Tym E, Mountjow CQ, et al. CAMDEX- A standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia. Br JPsychiatry 1986; 149: 698-709 32. Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A practical method for grading the cognitive state of patients for the clinician J Psychiat Res 1975; 12: 189-98. 33 Schaie KW. In. Schaie KW, ed Longitudinal studies of adult psychological development. New York: Guildford Press, 1983 34. Jenkyn LR, Reeves AG, Warren T, et al. Neurologic signs in senescence Arch Neurol
1985, 42: 1154-57 Benign senescent forgetfulness In: Katzman R, Terry RD, Bicks KL, eds Aging, vol 7. Alzheimer’s disease: Senile dementia and related disorders. New York: Raven Press, 1978 36. Rowe JW, Kahn RL. Human aging: Usual and successful. Science 1987; 237: 143-49. 37 Pickering GW High blood pressure. New York Raven Press, 1955. 38. Barker DJP, Rose G. Epidemiology in medical practice Edinburgh- Churchill Livingstone, 1984 35. Kral VA.