- Email: [email protected]
Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease
3
Mallat Z, Tedgui A, Fontaliran F, Frank R, Durigon M, Fontaine G. Evidence of apoptosis in arrhythmogenic right ventricular dysplasia. N Engl J Med 1996; 335: 1190–96. 4 Tews DS, Goebel HH. DNA-fragmentation and expression of apoptosis-related proteins in muscular dystrophies. Neuropathol Appl Neurobiol 1997; 23: 331–38. 5 Strasser H, Frauscher F, Helweg G, Colleselli K, Reissigl A, Bartsch G. Transurethral ultrasound: evaluation of anatomy and function of the rhabdosphincter of the male urethra. J Urol 1999; 159: 100–05.
Departments of Urology (H Strasser MD, G Bartsch MD ), Internal Medicine (M Tiefenthaler MD, G Konwalinka MD), and Forensic Medicine (M Steinlechner MD), University of Innsbruck, A-6020 Innsbruck, Austria Correspondence to: Dr Hannes Strasser (e-mail: [email protected])
Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer’s disease Margaret M Esiri, Zsuzsanna Nagy, Maria Z Smith, Lin Barnetson, A David Smith Cerebrovascular disease and Alzheimer’s disease commonly occur together in the elderly and each may contribute to dementia. Here we present evidence that cerebrovascular disease significantly worsens cognitive performance in the earliest stages of Alzheimer’s disease.
There is much interest in understanding how cerebrovascular disease may interact with Alzheimer’s disease to produce dementia. A study of 102 elderly nuns in the USA1 found that in 61, whose brains at necropsy harboured sufficient amyloid plaques to satisfy Khachaturian2 criteria for the neuropathological diagnosis of Alzheimer’s diease, the expression of clinical dementia was crucially dependent on whether or not there were subcortical lacunes in the brain. 93% of those with one or more lacunes had dementia compared with 57% of those without lacunes or infarcts. This study and another from our group3 also indicated that a given level of cognitive deficit occurs with less neurofibrillary pathology in Alzheimer’s disease if cerebrovascular disease is present than if it is absent. We provide additional evidence that cerebrovascular disease can enhance the capacity of Alzheimer’s disease pathology, particularly in its earliest stages, to promote dementia. We divided the first 103 consecutive cases in the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort, in which no pathology or Alzheimertype pathology with or without cerebrovascular disease was found at necropsy and which had been studied longitudinally in life, into four subdivisions based on the Braak staging procedure4 for determining severity of Alzheimer’s disease: controls with no neuritic pathology, entorhinal (stages 1 and 2), limbic (stages 3 and 4), and neocortical (stages 5 and 6). Patients with only Alzheimertype pathology were normal or had marginally reduced cognitive function on the Cambridge cognitive examination5 scale at the mild entorhinal stage of the disease, but if additional cerebrovascular disease was also present there was a significant reduction in the Cambridge cognitive examination score (normal range 80–107) in entorhinal Alzheimer’s disease (figure). At limbic and neocortical stages of Alzheimer’s disease a substantial cognitive deficit was present even in the absence of cerebrovascular disease, and if such disease was present the cognitive deficit was not substantially increased (figure).
THELANCET • Vol 354 • September 11, 1999
Cognitive function at different stages of Alzheimer’s disease Values shown are means (SE). *Significant difference compared with Alzheimer’s disease alone and controls (p=0·02).
Additional cerebrovascular disease took several forms. First, there were infarcts varying in size involving lobar cortex and adjacent white matter, present in seven cases. Second, subcortical lacunes or microinfarcts in cortex, white matter, or deep grey matter were present in 14 cases. Third, subcortical small-vessel disease in which widened perivascular spaces, with or without macrophage accumulations, were accompanied by patchy pallor of myelin staining in white matter, was present in all 24 patients with cerebrovascular disease, and in three patients this was the only form of vascular disease present. Forms of vascular disease in all these subcategories occurred at all Braak stages of Alzheimer’s disease, but the numbers of cases with subcategories of vascular disease in the different Braak stages of Alzheimer’s disease were too small to allow statistical comparisons. Alzheimer’s disease and cerebrovascular disease are both very common in old age. The early, entorhinal, stages of Alzheimer’s disease, which do not necessarily progress over time to more advanced stages, are generally considered to
919
be without symptoms or associated with little evidence of dementia. However, our findings suggest that cerebrovascular disease has a greater capacity to influence cognitive performance at these early stages of Alzheimer’s disease than at more advanced stages of the disease. We thank Catharine Joachim for her neuropathological assessments of OPTIMA cases. This work was supported by a financial grant from Bristol-Myers Squibb. 1
Snowdon DA, Greiner LH, Mortimer JA, et al. Brain infarction and the clinical expression of Alzheimer’s disease. JAMA 1997; 277: 813–17. 2 Khachaturian Z. Diagnosis of Alzheimer’s disease. Arch Neurol 1985; 42: 1097–105. 3 Nagy Z, Esiri MM, Jobst KA, et al. The effects of additional pathology on the cognitive deficit in Alzheimer’s disease. J Neuropathol Exp Neurol 1997; 56: 165–70. 4 Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 1991; 82: 239–59. 5 Roth M, Tym E, Mountjoy CQ, et al. A standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia. Br J Psychiatry 1986; 149: 698–709.
Department of Neuropathology, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK (Prof M M Esiri DM, Z Nagy DPhil, M Z Smith BA, C Joachim MD, L Barnetson BA, A D Smith DSc) Correspondence to: Prof Margaret M Esiri
Residential proximity to industry and adverse birth outcomes R S Bhopal, J A Tate, C Foy, S Moffatt, P R Phillimore We studied birth statistics in women living at varying proximity to major steel and petrochemical industries in Teesside, UK. We found no evidence to support the hypothesis that living close to these major industries led to adverse birth outcomes.
In studying the effect of industrial pollution on birth outcomes epidemiology is close to its limits.1 Judgments on cause and effect in such studies are controversial.1–3 We previously found no association between residential proximity to a coking plant and birth outcome.4 We examined birth outcomes in women living near major steel and petrochemical industries in Teesside, UK. 5 Residential proximity to industry was our proxy for exposure to industrial pollution from local industries, an approach supported by air-quality data and a land-use survey. 5 Our populations lived at varying distances from industry, but were similar in terms of factors such as smoking, occupation, and socioeconomic status. 27 neighbourhoods,
19 in Teesside (1991 population 77 330) and eight in Sunderland (population 43 485), were aggregated into zones (A, B, and C in Teesside with A closest to industry and C furthest, and S in Sunderland). A prerequisite for our considering an association potentially causal was both a gradient across Teesside (highest rates in zone A, lowest in zone C) and higher rates in Teesside than in zone S, the reference area. Postcoded birth data (1981–91) were obtained from the Office of Population Censuses and Surveys and fetal abnormality data (1986–93) were obtained from the congenital abnormalities register at the Maternity Surveys Office, Newcastle upon Tyne, which follows and contributes to the EUROCAT (European Registration of Congenital Anomalies) register. The register excludes isolated minor congenital abnormalities including skin tags, birthmarks, hypospadia. Proportions of stillborn and lowbirthweight babies were calculated with all births as the denominator. The denominator for the congenital abnormality rate was all births, stillbirths, and terminations. Study participants were linked to geographical areas by means of the program Postcoderx, which uses postcodes of residence to assign the enumeration district code, the smallest administrative area for which census data were available. At the time of the study the numbers of births in 1992 and 1993 were unavailable, so we estimated these from birth data for 1986–91. There was a trend in low birthweight across zones A, B, and C but in the opposite direction to that hypothesised (table). Zones A, B, and C together had a higher proportion of low-birthweight births than zone S. Odds ratios were higher in zones A, B, and C than in zone S. There was no trend in stillbirths across zones A, B, and C, and zone S had a higher stillbirth rate than the Teesside zones together. Odds ratios were lower in zones A, B, and C than in zone S. There were no important differences in sex ratio or fetal abnormality rate either across the Teesside zones or between them and zone S. Our data did not support a potentially causal role for local industrial pollution in adverse birth outcome in Teesside. This finding is unlikely to be artefact. The study period, size of population, and number of cases were large for studies examining the impact of air pollution in local areas. Errors in datasets, such as incomplete registration, would be more likely to lead to spurious associations than to no assocation in the direction hypothesised. One characteristic of our work4,5 is that our comparison populations were similar in socioeconomic characteristics. For a postulated association in which effects are subtle and epidemiology is near its limits,1 studies with negative
Zone A (n=4766)
Zone B (n=7487)
Zone C (n=6052)
p*
A, B, and C combined (n=18 305)
Zone S (n=9060)
p†
Low birthweight % <2500 g Odds ratio (95% CI) Number of cases
7·8 1·13 (0·99–1·30) 370
8·0 1·18 (1·05–1·32) 601
8·7 1·29 (1·14–1·46) 529
0·06
8·2 1·20 (1·09–1·33) 1500
6·9 1·00 626
0·0002
Stillbirth % stillborn Odds ratio (95% CI) Number of cases
0·5 0·64 (0·40–1·04) 22
0·6 0·86 (0·59–1·25) 46
0·4 0·55 (0·35–0·88) 24
0·54
0·5 0·70 (0·51–0·96) 92
0·7 1·00 65
0·03
Sex ratio % male Odds ratio (95% CI)
50 0·96 (0·90–1·03)
52 1·03 (0·97–1·10)
51 1·01 (0·95–1·08)
0·27
51 1·01 (0·96–1·06)
51 1·00
0·81
Fetal abnormality Rate per 1000 births Odds ratio (95% CI) Number of cases
16·6 1·15 (0·83–1·59) 60
17·2 1·19 (0·90–1·59) 97
12·6 0·87 (0·63–1·21) 57
0·13
15·5 1·08 (0·84–1·37) 241
14·5 1·00 95
0·56
n=number of births. *A, B, C by 2 test for trend. †ABC vs S.
Low-birthweight births, stillbirths, and sex ratio (1981–91) and fetal abnormality rates (1986–93)
920
THELANCET • Vol 354 • September 11, 1999
Mallat Z, Tedgui A, Fontaliran F, Frank R, Durigon M, Fontaine G. Evidence of apoptosis in arrhythmogenic right ventricular dysplasia. N Engl J Med 1996; 335: 1190–96. 4 Tews DS, Goebel HH. DNA-fragmentation and expression of apoptosis-related proteins in muscular dystrophies. Neuropathol Appl Neurobiol 1997; 23: 331–38. 5 Strasser H, Frauscher F, Helweg G, Colleselli K, Reissigl A, Bartsch G. Transurethral ultrasound: evaluation of anatomy and function of the rhabdosphincter of the male urethra. J Urol 1999; 159: 100–05.
Departments of Urology (H Strasser MD, G Bartsch MD ), Internal Medicine (M Tiefenthaler MD, G Konwalinka MD), and Forensic Medicine (M Steinlechner MD), University of Innsbruck, A-6020 Innsbruck, Austria Correspondence to: Dr Hannes Strasser (e-mail: [email protected])
Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer’s disease Margaret M Esiri, Zsuzsanna Nagy, Maria Z Smith, Lin Barnetson, A David Smith Cerebrovascular disease and Alzheimer’s disease commonly occur together in the elderly and each may contribute to dementia. Here we present evidence that cerebrovascular disease significantly worsens cognitive performance in the earliest stages of Alzheimer’s disease.
There is much interest in understanding how cerebrovascular disease may interact with Alzheimer’s disease to produce dementia. A study of 102 elderly nuns in the USA1 found that in 61, whose brains at necropsy harboured sufficient amyloid plaques to satisfy Khachaturian2 criteria for the neuropathological diagnosis of Alzheimer’s diease, the expression of clinical dementia was crucially dependent on whether or not there were subcortical lacunes in the brain. 93% of those with one or more lacunes had dementia compared with 57% of those without lacunes or infarcts. This study and another from our group3 also indicated that a given level of cognitive deficit occurs with less neurofibrillary pathology in Alzheimer’s disease if cerebrovascular disease is present than if it is absent. We provide additional evidence that cerebrovascular disease can enhance the capacity of Alzheimer’s disease pathology, particularly in its earliest stages, to promote dementia. We divided the first 103 consecutive cases in the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort, in which no pathology or Alzheimertype pathology with or without cerebrovascular disease was found at necropsy and which had been studied longitudinally in life, into four subdivisions based on the Braak staging procedure4 for determining severity of Alzheimer’s disease: controls with no neuritic pathology, entorhinal (stages 1 and 2), limbic (stages 3 and 4), and neocortical (stages 5 and 6). Patients with only Alzheimertype pathology were normal or had marginally reduced cognitive function on the Cambridge cognitive examination5 scale at the mild entorhinal stage of the disease, but if additional cerebrovascular disease was also present there was a significant reduction in the Cambridge cognitive examination score (normal range 80–107) in entorhinal Alzheimer’s disease (figure). At limbic and neocortical stages of Alzheimer’s disease a substantial cognitive deficit was present even in the absence of cerebrovascular disease, and if such disease was present the cognitive deficit was not substantially increased (figure).
THELANCET • Vol 354 • September 11, 1999
Cognitive function at different stages of Alzheimer’s disease Values shown are means (SE). *Significant difference compared with Alzheimer’s disease alone and controls (p=0·02).
Additional cerebrovascular disease took several forms. First, there were infarcts varying in size involving lobar cortex and adjacent white matter, present in seven cases. Second, subcortical lacunes or microinfarcts in cortex, white matter, or deep grey matter were present in 14 cases. Third, subcortical small-vessel disease in which widened perivascular spaces, with or without macrophage accumulations, were accompanied by patchy pallor of myelin staining in white matter, was present in all 24 patients with cerebrovascular disease, and in three patients this was the only form of vascular disease present. Forms of vascular disease in all these subcategories occurred at all Braak stages of Alzheimer’s disease, but the numbers of cases with subcategories of vascular disease in the different Braak stages of Alzheimer’s disease were too small to allow statistical comparisons. Alzheimer’s disease and cerebrovascular disease are both very common in old age. The early, entorhinal, stages of Alzheimer’s disease, which do not necessarily progress over time to more advanced stages, are generally considered to
919
be without symptoms or associated with little evidence of dementia. However, our findings suggest that cerebrovascular disease has a greater capacity to influence cognitive performance at these early stages of Alzheimer’s disease than at more advanced stages of the disease. We thank Catharine Joachim for her neuropathological assessments of OPTIMA cases. This work was supported by a financial grant from Bristol-Myers Squibb. 1
Snowdon DA, Greiner LH, Mortimer JA, et al. Brain infarction and the clinical expression of Alzheimer’s disease. JAMA 1997; 277: 813–17. 2 Khachaturian Z. Diagnosis of Alzheimer’s disease. Arch Neurol 1985; 42: 1097–105. 3 Nagy Z, Esiri MM, Jobst KA, et al. The effects of additional pathology on the cognitive deficit in Alzheimer’s disease. J Neuropathol Exp Neurol 1997; 56: 165–70. 4 Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 1991; 82: 239–59. 5 Roth M, Tym E, Mountjoy CQ, et al. A standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia. Br J Psychiatry 1986; 149: 698–709.
Department of Neuropathology, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK (Prof M M Esiri DM, Z Nagy DPhil, M Z Smith BA, C Joachim MD, L Barnetson BA, A D Smith DSc) Correspondence to: Prof Margaret M Esiri
Residential proximity to industry and adverse birth outcomes R S Bhopal, J A Tate, C Foy, S Moffatt, P R Phillimore We studied birth statistics in women living at varying proximity to major steel and petrochemical industries in Teesside, UK. We found no evidence to support the hypothesis that living close to these major industries led to adverse birth outcomes.
In studying the effect of industrial pollution on birth outcomes epidemiology is close to its limits.1 Judgments on cause and effect in such studies are controversial.1–3 We previously found no association between residential proximity to a coking plant and birth outcome.4 We examined birth outcomes in women living near major steel and petrochemical industries in Teesside, UK. 5 Residential proximity to industry was our proxy for exposure to industrial pollution from local industries, an approach supported by air-quality data and a land-use survey. 5 Our populations lived at varying distances from industry, but were similar in terms of factors such as smoking, occupation, and socioeconomic status. 27 neighbourhoods,
19 in Teesside (1991 population 77 330) and eight in Sunderland (population 43 485), were aggregated into zones (A, B, and C in Teesside with A closest to industry and C furthest, and S in Sunderland). A prerequisite for our considering an association potentially causal was both a gradient across Teesside (highest rates in zone A, lowest in zone C) and higher rates in Teesside than in zone S, the reference area. Postcoded birth data (1981–91) were obtained from the Office of Population Censuses and Surveys and fetal abnormality data (1986–93) were obtained from the congenital abnormalities register at the Maternity Surveys Office, Newcastle upon Tyne, which follows and contributes to the EUROCAT (European Registration of Congenital Anomalies) register. The register excludes isolated minor congenital abnormalities including skin tags, birthmarks, hypospadia. Proportions of stillborn and lowbirthweight babies were calculated with all births as the denominator. The denominator for the congenital abnormality rate was all births, stillbirths, and terminations. Study participants were linked to geographical areas by means of the program Postcoderx, which uses postcodes of residence to assign the enumeration district code, the smallest administrative area for which census data were available. At the time of the study the numbers of births in 1992 and 1993 were unavailable, so we estimated these from birth data for 1986–91. There was a trend in low birthweight across zones A, B, and C but in the opposite direction to that hypothesised (table). Zones A, B, and C together had a higher proportion of low-birthweight births than zone S. Odds ratios were higher in zones A, B, and C than in zone S. There was no trend in stillbirths across zones A, B, and C, and zone S had a higher stillbirth rate than the Teesside zones together. Odds ratios were lower in zones A, B, and C than in zone S. There were no important differences in sex ratio or fetal abnormality rate either across the Teesside zones or between them and zone S. Our data did not support a potentially causal role for local industrial pollution in adverse birth outcome in Teesside. This finding is unlikely to be artefact. The study period, size of population, and number of cases were large for studies examining the impact of air pollution in local areas. Errors in datasets, such as incomplete registration, would be more likely to lead to spurious associations than to no assocation in the direction hypothesised. One characteristic of our work4,5 is that our comparison populations were similar in socioeconomic characteristics. For a postulated association in which effects are subtle and epidemiology is near its limits,1 studies with negative
Zone A (n=4766)
Zone B (n=7487)
Zone C (n=6052)
p*
A, B, and C combined (n=18 305)
Zone S (n=9060)
p†
Low birthweight % <2500 g Odds ratio (95% CI) Number of cases
7·8 1·13 (0·99–1·30) 370
8·0 1·18 (1·05–1·32) 601
8·7 1·29 (1·14–1·46) 529
0·06
8·2 1·20 (1·09–1·33) 1500
6·9 1·00 626
0·0002
Stillbirth % stillborn Odds ratio (95% CI) Number of cases
0·5 0·64 (0·40–1·04) 22
0·6 0·86 (0·59–1·25) 46
0·4 0·55 (0·35–0·88) 24
0·54
0·5 0·70 (0·51–0·96) 92
0·7 1·00 65
0·03
Sex ratio % male Odds ratio (95% CI)
50 0·96 (0·90–1·03)
52 1·03 (0·97–1·10)
51 1·01 (0·95–1·08)
0·27
51 1·01 (0·96–1·06)
51 1·00
0·81
Fetal abnormality Rate per 1000 births Odds ratio (95% CI) Number of cases
16·6 1·15 (0·83–1·59) 60
17·2 1·19 (0·90–1·59) 97
12·6 0·87 (0·63–1·21) 57
0·13
15·5 1·08 (0·84–1·37) 241
14·5 1·00 95
0·56
n=number of births. *A, B, C by 2 test for trend. †ABC vs S.
Low-birthweight births, stillbirths, and sex ratio (1981–91) and fetal abnormality rates (1986–93)
920
THELANCET • Vol 354 • September 11, 1999