Prospective study of type 2 diabetes and cognitive decline in women aged 70-81 years
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《英国医生杂志》
1 Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA, 2 Channing Lab, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston
Correspondence to: G Logroscino glogrosc@hsph.harvard.edu
Abstract
Several population based studies have shown that type 2 diabetes increases the risk of dementia.1-5 Cognitive decline is an intermediate stage between normal ageing and dementia.6 As dementia may be most effectively delayed in its initial stages, identifying diabetes as a modifiable risk factor for early cognitive decline could be of major public health importance. Estimates in the United States indicate that delaying onset of dementia by one year could lead to 800 000 fewer cases after 50 years.7
Though many investigations have examined diabetes in relation to early cognitive decline,5 8-19 only one large prospective study has focused on women.8 Type 2 diabetes disproportionately affects older women and is a stronger risk factor for cardiovascular disease in women than in men.20 As cardiovascular disease is an independent risk factor for cognitive decline, we need to determine the impact of diabetes on cognition in women.20 Moreover, few studies have evaluated the influence of different treatments for diabetes on the association between type 2 diabetes and cognition.
We assessed the associations between type 2 diabetes, different treatments for diabetes, and cognitive function in more than 16 000 women.
Methods
At baseline interview 7.3% (n = 1394) of the women had type 2 diabetes, with a mean duration of 12 years since diagnosis. Of the 1248 women with diabetes who completed the most recent questionnaire, 901 reported recent medication for management of diabetes (294 (33%) insulin, 607 (67%) oral hypoglycaemic agents). As expected, women with diabetes had higher prevalence of several comorbid conditions (hypertension, high cholesterol, heart disease, obesity, depression) than women without diabetes (table 1), and used hormone therapy less and drank less alcohol. On every cognitive test, mean baseline scores were lower for women with diabetes (table 2).
Table 1 Characteristics of women aged 70-81 years, according to type 2 diabetes. Figures are percentage of respondents unless stated otherwise*
Table 2 Mean cognitive test scores at baseline in women aged 70-81, according to type 2 diabetes. Figures are means (SD)
We focused analyses on two measures of general cognitive function: the TICS and the global score (table 3). After we adjusted for potential confounding factors, women with diabetes were at 25-35% increased odds of poor baseline score compared with women without diabetes (odds ratio 1.34, 95% confidence interval 1.14 to 1.57, for TICS and 1.26, 1.06 to 1.51, for global score). Findings were consistent when we examined mean differences in scores; the mean score for women with diabetes was lower by -0.42 points, -0.58 to -0.27 points, on the TICS and by -0.09 units, -0.12 to -0.05 units, on the global score compared with women without diabetes. Associations became stronger with longer duration of diabetes. For those with diabetes for 15 years the odds of poor cognitive performance was 50% higher than for women without diabetes (1.52, 1.15 to 1.99, and 1.49, 1.11 to 2.00, respectively).
Odds of poor performance also seemed to differ across treatment groups (table 3). Compared with women without diabetes, we found high odds of poor performance for women with diabetes who did not report pharmaceutical treatment (1.71, 1.28 to 2.28, and 1.45, 1.04 to 2.02, respectively). Those taking insulin also had modestly increased odds of poor cognition (1.20, 0.85 to 1.70, and 1.38, 0.97 to 1.95, respectively). In the more powerful analyses of mean differences, the worst performance was among women using insulin (mean differences -0.40, -0.72 to -0.09, and -0.11, -0.18 to -0.03, respectively). In contrast, those taking oral medications had similar odds of poor cognitive performance as those without diabetes (odds ratios 1.06, 0.81 to 1.37, and 0.99, 0.74 to 1.33, respectively) and had the smallest mean difference in score (mean differences -0.35, -0.58 to -0.13, and -0.06, -0.11 to -0.01, respectively).
As cognitive impairment may be a cause rather than a consequence of not taking medications, we also examined use of medication at time of diagnosis (average of 12 years before cognitive assessment). However, results were similar: the odds ratios for poor score were 1.61, 1.19 to 2.16, and 1.43, 1.02 to 2.00, respectively, for women with diabetes who were not taking medication at diagnosis compared with women without diabetes.
In addition, as duration of diabetes, medication use, and level of control are correlated we conducted additional analyses to try to assess their independent effects. The results for duration of diabetes were largely similar after we adjusted for medication use, and results for medication use were largely unchanged after we included a term for duration in the model or stratified by duration of diabetes. For example, among women with diabetes, those not taking medication had a higher risk of poor cognitive performance on the TICS compared with those taking oral medication both in the group with duration of diabetes < 10 years (1.73, 1.01 to 2.98) and 10 years (1.90, 1.04 to 3.48). Furthermore, although we did not have detailed information on level of control (for example, data on haemoglobin A1c concentration), all results were generally unchanged when we excluded data from women with metabolic complications (for instance, those with severely uncontrolled disease).
Finally, we restricted analyses to participants who did not report any difficulty with hearing (n = 12 099) to reduce confounding by hearing status. The results were similar when we compared women with and without diabetes (1.45, 1.18 to 1.78, and 1.37, 1.10 to 1.71, respectively).
Prospective analyses of decline
Although cognitive decline was measured over just a two year period, we observed a significantly increased odds of substantial decline on the TICS (1.26, 1.03 to 1.54) for women compared with women without type 2 diabetes (table 4). However, we observed little overall relation between diabetes and decline on the global score (1.11, 0.90 to 1.37). Similarly, mean decline was greater among women with diabetes by -0.17 points (-0.33 to -0.01) on the TICS but was comparable in the two groups on the global score (mean difference in decline -0.01, -0.04 to 0.03). In addition, qualitative relations with longer duration diabetes and use of medication were generally similar to those observed with baseline cognitive function.
Discussion
Ott A, Stolk RP, Van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: the Rotterdam study. Neurology 1999;53: 1937-42.
Leibson CL, Rocca, WA, Hanson VA, Cha R, Kokmen E, O'Brien PC, et al. Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol 1997;145: 301-8.
Curb JD, Rodriguez BL, Abbott RD, Petrovitch H, Ross GW, Masaki KH, et al. Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance. Neurology 1999;52: 971-5.
Luchsinger JA, Tang MX, Stern Y, Shea S, Mayeaux R. Diabetes mellitus and risk of Alzheimer's disease and dementia with stroke in a multiethnic cohort. Am J Epidemiol 2001;154: 635-41.
MacKnight C, Rockwood K, Awalt E, McDowell I. Diabetes mellitus and the risk of dementia, Alzheimer's disease and vascular cognitive impairment in the Canadian study of health and aging. Dement Geriatr Cogn Disord 2002;14: 77-83.
Bozoki A, Giordani B, Heidebrink JL, Berent S, Foster NL. Mild cognitive impairments predict dementia in nondemented elderly patients with memory loss. Arch Neurol 2001;58: 411-6.
Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Pub Health 1998;88: 1337-42.
Gregg, EW, Yaffe K, Cauley JA, Rolka DB, Blackwell TL, Narayan KM, et al. Is diabetes associated with cognitive impairment and cognitive decline among older women? Study of Osteoporotic Fractures Research Group. Arch Intern Med 2000;160: 174-80.
Knopman D, Boland LL, Mosley T, Howard G, Liao D, Szklo M, et al. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology 2001;56: 42-8.
Kalmijn S, Feskens EJ, Launer LJ, Stijnen T, Kromhout D. Glucose intolerance, hyperinsulinaemia and cognitive function in a general population of elderly men. Diabetologia 1995;38: 1096-102.
Scott RD, Kritz-Silverstein D, Barrett-Connor E, Wiederholt WC. The association of non-insulin-dependent diabetes mellitus and cognitive function in an older cohort. J Am Geriatr Soc 1998;46: 1217-22.
Fontbonne A, Berr C, Ducimetiere P, Alperovitch A. Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects: results of the epidemiology of vascular aging study. Diabetes Care 2001;24: 366-70.
Stolk RP, Breteler MM, Ott A, Pols HA, Lamberts, SW, Grobbee DE, et al. Insulin and cognitive function in an elderly population. The Rotterdam study. Diabetes Care 1997;20: 792-5.
Elias PK, Elias MF, D'Agostino RB, Cupples LA, Wilson PW, Silbershatz H, et al. NIDDM and blood pressure as risk factors for poor cognitive performance. The Framingham study. Diabetes Care 1997;20: 1388-95.
Rodriguez-Saldana J, Morley JE, Reynoso MT, Medina CA, Salazar P, Cruz E, et al. Diabetes mellitus in a subgroup of older Mexicans: prevalence, association with cardiovascular risk factors, functional and cognitive impairment, and mortality. J Am Geriatr Soc 2002;50: 111-6.
Nguyen HT, Black SA, Ray LA, Espino DV, Markides KS. Predictors of decline in MMSE scores among older Mexican Americans. J Gerontol A Biol Sci Med Sci 2002;57: M181-5.
Wu JH, Haan MN, Liang J, Ghosh D, Gonzalez HM, Herman WH. Impact of diabetes on cognitive function among older Latinos: a population-based cohort study. J Clin Epidemiol 2003;56: 686-93.
Vanhanen M, Kuusisto J, Koivisto K, Mykkanen L, Helkala EL, Hanninen T, et al. Type-2 diabetes and cognitive function in a non-demented population. Acta Neurol Scand 1999;100: 97-101.
Lindeman RD, Romero LJ, LaRue A, Yau CL, Schade DS, Koehler KM, et al. A biethnic community survey of cognition in participants with type 2 diabetes, impaired glucose tolerance, and normal glucose tolerance: the New Mexico elder health survey. Diabetes Care 2001;24: 1567-72.
Coker LH, Shumaker SA. Type 2 diabetes mellitus and cognition: an understudied issue in women's health. J Psychosom Research 2003;54: 129-39.
Kang JH, Grodstein F. Regular use of nonsteroidal anti-inflammatory drugs and cognitive function in aging women. Neurology 2003;60: 1591-7.
Brandt J, Spencer M, Folstein M. The telephone interview for cognitive status. Neuropsychiatry Neuropsychol Behav Neurol 1988;1: 111-7.
National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979;28: 1039-57.
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2000;suppl 1: S4-19.
Manson JE, Rimm EB, Stampfer MJ, Colditz GA, Willett WC, Krolewski AS, et al. Physical activity and incidence of non-insulin-dependent diabetes mellitus in women. Lancet 1991;338: 774-8.
Vickers A, Altman D. Analysing controlled trials with baseline and follow-up measurements. BMJ 2001;323: 1123-4.
Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA 2003;100: 4162-7.
Watson GS, Peskind ER, Asthana S, Purganan K, Wait C, Chapman D, et al. Insulin increases CSF Abeta42 levels in normal older adults. Neurology 2003;60: 1899-903.
Testa MA, Simonson DC. Health economic benefits and quality of life during improved glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled, double-blind trial. JAMA 1998;280: 1490-6.
Wu JH, Haan MN, Liang J, Ghosh D, Gonzalez HM, Herman WH. Impact of antidiabetic medications on physical and cognitive functioning of older Mexican Americans with diabetes mellitus: a population-based cohort study. Ann Epidemiol 2003;13: 369-76.(Giancarlo Logroscino, ass)
Correspondence to: G Logroscino glogrosc@hsph.harvard.edu
Abstract
Several population based studies have shown that type 2 diabetes increases the risk of dementia.1-5 Cognitive decline is an intermediate stage between normal ageing and dementia.6 As dementia may be most effectively delayed in its initial stages, identifying diabetes as a modifiable risk factor for early cognitive decline could be of major public health importance. Estimates in the United States indicate that delaying onset of dementia by one year could lead to 800 000 fewer cases after 50 years.7
Though many investigations have examined diabetes in relation to early cognitive decline,5 8-19 only one large prospective study has focused on women.8 Type 2 diabetes disproportionately affects older women and is a stronger risk factor for cardiovascular disease in women than in men.20 As cardiovascular disease is an independent risk factor for cognitive decline, we need to determine the impact of diabetes on cognition in women.20 Moreover, few studies have evaluated the influence of different treatments for diabetes on the association between type 2 diabetes and cognition.
We assessed the associations between type 2 diabetes, different treatments for diabetes, and cognitive function in more than 16 000 women.
Methods
At baseline interview 7.3% (n = 1394) of the women had type 2 diabetes, with a mean duration of 12 years since diagnosis. Of the 1248 women with diabetes who completed the most recent questionnaire, 901 reported recent medication for management of diabetes (294 (33%) insulin, 607 (67%) oral hypoglycaemic agents). As expected, women with diabetes had higher prevalence of several comorbid conditions (hypertension, high cholesterol, heart disease, obesity, depression) than women without diabetes (table 1), and used hormone therapy less and drank less alcohol. On every cognitive test, mean baseline scores were lower for women with diabetes (table 2).
Table 1 Characteristics of women aged 70-81 years, according to type 2 diabetes. Figures are percentage of respondents unless stated otherwise*
Table 2 Mean cognitive test scores at baseline in women aged 70-81, according to type 2 diabetes. Figures are means (SD)
We focused analyses on two measures of general cognitive function: the TICS and the global score (table 3). After we adjusted for potential confounding factors, women with diabetes were at 25-35% increased odds of poor baseline score compared with women without diabetes (odds ratio 1.34, 95% confidence interval 1.14 to 1.57, for TICS and 1.26, 1.06 to 1.51, for global score). Findings were consistent when we examined mean differences in scores; the mean score for women with diabetes was lower by -0.42 points, -0.58 to -0.27 points, on the TICS and by -0.09 units, -0.12 to -0.05 units, on the global score compared with women without diabetes. Associations became stronger with longer duration of diabetes. For those with diabetes for 15 years the odds of poor cognitive performance was 50% higher than for women without diabetes (1.52, 1.15 to 1.99, and 1.49, 1.11 to 2.00, respectively).
Odds of poor performance also seemed to differ across treatment groups (table 3). Compared with women without diabetes, we found high odds of poor performance for women with diabetes who did not report pharmaceutical treatment (1.71, 1.28 to 2.28, and 1.45, 1.04 to 2.02, respectively). Those taking insulin also had modestly increased odds of poor cognition (1.20, 0.85 to 1.70, and 1.38, 0.97 to 1.95, respectively). In the more powerful analyses of mean differences, the worst performance was among women using insulin (mean differences -0.40, -0.72 to -0.09, and -0.11, -0.18 to -0.03, respectively). In contrast, those taking oral medications had similar odds of poor cognitive performance as those without diabetes (odds ratios 1.06, 0.81 to 1.37, and 0.99, 0.74 to 1.33, respectively) and had the smallest mean difference in score (mean differences -0.35, -0.58 to -0.13, and -0.06, -0.11 to -0.01, respectively).
As cognitive impairment may be a cause rather than a consequence of not taking medications, we also examined use of medication at time of diagnosis (average of 12 years before cognitive assessment). However, results were similar: the odds ratios for poor score were 1.61, 1.19 to 2.16, and 1.43, 1.02 to 2.00, respectively, for women with diabetes who were not taking medication at diagnosis compared with women without diabetes.
In addition, as duration of diabetes, medication use, and level of control are correlated we conducted additional analyses to try to assess their independent effects. The results for duration of diabetes were largely similar after we adjusted for medication use, and results for medication use were largely unchanged after we included a term for duration in the model or stratified by duration of diabetes. For example, among women with diabetes, those not taking medication had a higher risk of poor cognitive performance on the TICS compared with those taking oral medication both in the group with duration of diabetes < 10 years (1.73, 1.01 to 2.98) and 10 years (1.90, 1.04 to 3.48). Furthermore, although we did not have detailed information on level of control (for example, data on haemoglobin A1c concentration), all results were generally unchanged when we excluded data from women with metabolic complications (for instance, those with severely uncontrolled disease).
Finally, we restricted analyses to participants who did not report any difficulty with hearing (n = 12 099) to reduce confounding by hearing status. The results were similar when we compared women with and without diabetes (1.45, 1.18 to 1.78, and 1.37, 1.10 to 1.71, respectively).
Prospective analyses of decline
Although cognitive decline was measured over just a two year period, we observed a significantly increased odds of substantial decline on the TICS (1.26, 1.03 to 1.54) for women compared with women without type 2 diabetes (table 4). However, we observed little overall relation between diabetes and decline on the global score (1.11, 0.90 to 1.37). Similarly, mean decline was greater among women with diabetes by -0.17 points (-0.33 to -0.01) on the TICS but was comparable in the two groups on the global score (mean difference in decline -0.01, -0.04 to 0.03). In addition, qualitative relations with longer duration diabetes and use of medication were generally similar to those observed with baseline cognitive function.
Discussion
Ott A, Stolk RP, Van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: the Rotterdam study. Neurology 1999;53: 1937-42.
Leibson CL, Rocca, WA, Hanson VA, Cha R, Kokmen E, O'Brien PC, et al. Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol 1997;145: 301-8.
Curb JD, Rodriguez BL, Abbott RD, Petrovitch H, Ross GW, Masaki KH, et al. Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance. Neurology 1999;52: 971-5.
Luchsinger JA, Tang MX, Stern Y, Shea S, Mayeaux R. Diabetes mellitus and risk of Alzheimer's disease and dementia with stroke in a multiethnic cohort. Am J Epidemiol 2001;154: 635-41.
MacKnight C, Rockwood K, Awalt E, McDowell I. Diabetes mellitus and the risk of dementia, Alzheimer's disease and vascular cognitive impairment in the Canadian study of health and aging. Dement Geriatr Cogn Disord 2002;14: 77-83.
Bozoki A, Giordani B, Heidebrink JL, Berent S, Foster NL. Mild cognitive impairments predict dementia in nondemented elderly patients with memory loss. Arch Neurol 2001;58: 411-6.
Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Pub Health 1998;88: 1337-42.
Gregg, EW, Yaffe K, Cauley JA, Rolka DB, Blackwell TL, Narayan KM, et al. Is diabetes associated with cognitive impairment and cognitive decline among older women? Study of Osteoporotic Fractures Research Group. Arch Intern Med 2000;160: 174-80.
Knopman D, Boland LL, Mosley T, Howard G, Liao D, Szklo M, et al. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology 2001;56: 42-8.
Kalmijn S, Feskens EJ, Launer LJ, Stijnen T, Kromhout D. Glucose intolerance, hyperinsulinaemia and cognitive function in a general population of elderly men. Diabetologia 1995;38: 1096-102.
Scott RD, Kritz-Silverstein D, Barrett-Connor E, Wiederholt WC. The association of non-insulin-dependent diabetes mellitus and cognitive function in an older cohort. J Am Geriatr Soc 1998;46: 1217-22.
Fontbonne A, Berr C, Ducimetiere P, Alperovitch A. Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects: results of the epidemiology of vascular aging study. Diabetes Care 2001;24: 366-70.
Stolk RP, Breteler MM, Ott A, Pols HA, Lamberts, SW, Grobbee DE, et al. Insulin and cognitive function in an elderly population. The Rotterdam study. Diabetes Care 1997;20: 792-5.
Elias PK, Elias MF, D'Agostino RB, Cupples LA, Wilson PW, Silbershatz H, et al. NIDDM and blood pressure as risk factors for poor cognitive performance. The Framingham study. Diabetes Care 1997;20: 1388-95.
Rodriguez-Saldana J, Morley JE, Reynoso MT, Medina CA, Salazar P, Cruz E, et al. Diabetes mellitus in a subgroup of older Mexicans: prevalence, association with cardiovascular risk factors, functional and cognitive impairment, and mortality. J Am Geriatr Soc 2002;50: 111-6.
Nguyen HT, Black SA, Ray LA, Espino DV, Markides KS. Predictors of decline in MMSE scores among older Mexican Americans. J Gerontol A Biol Sci Med Sci 2002;57: M181-5.
Wu JH, Haan MN, Liang J, Ghosh D, Gonzalez HM, Herman WH. Impact of diabetes on cognitive function among older Latinos: a population-based cohort study. J Clin Epidemiol 2003;56: 686-93.
Vanhanen M, Kuusisto J, Koivisto K, Mykkanen L, Helkala EL, Hanninen T, et al. Type-2 diabetes and cognitive function in a non-demented population. Acta Neurol Scand 1999;100: 97-101.
Lindeman RD, Romero LJ, LaRue A, Yau CL, Schade DS, Koehler KM, et al. A biethnic community survey of cognition in participants with type 2 diabetes, impaired glucose tolerance, and normal glucose tolerance: the New Mexico elder health survey. Diabetes Care 2001;24: 1567-72.
Coker LH, Shumaker SA. Type 2 diabetes mellitus and cognition: an understudied issue in women's health. J Psychosom Research 2003;54: 129-39.
Kang JH, Grodstein F. Regular use of nonsteroidal anti-inflammatory drugs and cognitive function in aging women. Neurology 2003;60: 1591-7.
Brandt J, Spencer M, Folstein M. The telephone interview for cognitive status. Neuropsychiatry Neuropsychol Behav Neurol 1988;1: 111-7.
National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979;28: 1039-57.
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2000;suppl 1: S4-19.
Manson JE, Rimm EB, Stampfer MJ, Colditz GA, Willett WC, Krolewski AS, et al. Physical activity and incidence of non-insulin-dependent diabetes mellitus in women. Lancet 1991;338: 774-8.
Vickers A, Altman D. Analysing controlled trials with baseline and follow-up measurements. BMJ 2001;323: 1123-4.
Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA 2003;100: 4162-7.
Watson GS, Peskind ER, Asthana S, Purganan K, Wait C, Chapman D, et al. Insulin increases CSF Abeta42 levels in normal older adults. Neurology 2003;60: 1899-903.
Testa MA, Simonson DC. Health economic benefits and quality of life during improved glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled, double-blind trial. JAMA 1998;280: 1490-6.
Wu JH, Haan MN, Liang J, Ghosh D, Gonzalez HM, Herman WH. Impact of antidiabetic medications on physical and cognitive functioning of older Mexican Americans with diabetes mellitus: a population-based cohort study. Ann Epidemiol 2003;13: 369-76.(Giancarlo Logroscino, ass)