The Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes Study (ACCORD-MIND): Rationale, Design, and Methods
2007; Elsevier BV; Volume: 99; Issue: 12 Linguagem: Inglês
10.1016/j.amjcard.2007.03.029
ISSN1879-1913
AutoresJeff D. Williamson, Michael E. Miller, R. Nick Bryan, Ronald M. Lazar, Laura H. Coker, Janice Johnson, Tali Cukierman, Karen R. Horowitz, Anne M. Murray, Lenore J. Launer,
Tópico(s)Neurological Disorders and Treatments
ResumoType 2 diabetes mellitus and cognitive impairment are 2 of the most common chronic conditions found in persons aged ≥60 years. Clinical studies have shown a greater prevalence of global cognitive impairment, incidence of cognitive decline, and incidence of Alzheimer disease in patients with type 2 diabetes. To date, there have been no randomized trials of the effects of long-term glycemic control on cognitive function and structural brain changes in patients with type 2 diabetes. The primary aim of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Memory in Diabetes Study (ACCORD-MIND) is to test whether there is a difference in the rate of cognitive decline and structural brain change in patients with diabetes treated with standard-care guidelines compared with those treated with intensive-care guidelines. This comparison will be made in a subsample of 2,977 patients with diabetes participating in the ongoing ACCORD trial, a clinical trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI) with support from the National Institute on Aging (NIA). Data from this ACCORD substudy on the possible beneficial or adverse effects of intensive treatment on cognitive function will be obtained from a 30-minute test battery, administered at baseline and 20-month and 40-month visits. In addition, full-brain magnetic resonance imaging will be performed on 630 participants at baseline and at 40 months to assess the relation between the ACCORD treatments and structural brain changes. The general aim of ACCORD-MIND is to determine whether the intensive treatment of diabetes, a major risk factor for Alzheimer disease and vascular dementia, can reduce the early decline in cognitive function that could later evolve into more cognitively disabling conditions. This report presents the design, rationale, and methods of the ACCORD-MIND substudy. Type 2 diabetes mellitus and cognitive impairment are 2 of the most common chronic conditions found in persons aged ≥60 years. Clinical studies have shown a greater prevalence of global cognitive impairment, incidence of cognitive decline, and incidence of Alzheimer disease in patients with type 2 diabetes. To date, there have been no randomized trials of the effects of long-term glycemic control on cognitive function and structural brain changes in patients with type 2 diabetes. The primary aim of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Memory in Diabetes Study (ACCORD-MIND) is to test whether there is a difference in the rate of cognitive decline and structural brain change in patients with diabetes treated with standard-care guidelines compared with those treated with intensive-care guidelines. This comparison will be made in a subsample of 2,977 patients with diabetes participating in the ongoing ACCORD trial, a clinical trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI) with support from the National Institute on Aging (NIA). Data from this ACCORD substudy on the possible beneficial or adverse effects of intensive treatment on cognitive function will be obtained from a 30-minute test battery, administered at baseline and 20-month and 40-month visits. In addition, full-brain magnetic resonance imaging will be performed on 630 participants at baseline and at 40 months to assess the relation between the ACCORD treatments and structural brain changes. The general aim of ACCORD-MIND is to determine whether the intensive treatment of diabetes, a major risk factor for Alzheimer disease and vascular dementia, can reduce the early decline in cognitive function that could later evolve into more cognitively disabling conditions. This report presents the design, rationale, and methods of the ACCORD-MIND substudy. The prevalence and incidence of type 2 diabetes mellitus increases with age.1Mokdad A.H. Bowman B.A. Ford E.S. Vinicor F. Marks J.S. Koplan J.P. The continuing epidemics of obesity and diabetes in the United States.JAMA. 2001; 286: 1195-1200Crossref PubMed Scopus (2236) Google Scholar, 2Wild S.W. Roglic G. Green A. Sicree R. King H. Global prevalence of diabetes.Diabetes Care. 2004; 27: 1047-1053Crossref PubMed Scopus (11710) Google Scholar Similarly, cognitive impairment is prevalent in older persons and increases with age. Cognitive impairment lowers the quality of life and can advance to dementia, a leading cause of long-term care placement.3National Institute on AgingNational Institutes of HealthProgress Report on Alzheimer's Disease. US Dept of Health and Human Services, Public Health Service, Bethesda, MD2000Google Scholar, 4Jagger C. Andersen K. Breteler M.M.B. Copeland J.R.M. Helmer C. Baldereschi M. Fratiglioni L. Lobo A. Soininen H. Hofman A. Launer L.J. Neurologic Diseases in the Elderly Research GroupPrognosis with dementia in Europe: a collaborative study of population-based cohorts.Neurology. 2000; 54: S16-S20PubMed Google Scholar, 5Magsi H. Malloy T. Underrecognition of cognitive impairment in assisted living facilities.J Am Geriatr Soc. 2005; 53: 295-298Crossref PubMed Scopus (55) Google Scholar Recent studies suggest that type 2 diabetes is a risk factor for cognitive impairment in older persons. Clinical studies have shown that patients with diabetes have impaired neuropsychological function.6Strachan M.W.J. Deary I.J. Ewing F.M.E. Friere B.M. Is type II diabetes associated with an increased risk of cognitive dysfunction?.Diabetes Care. 1997; 20: 438-445Crossref PubMed Scopus (438) Google Scholar, 7Coker L.H. Shumaker S.A. Type 2 diabetes mellitus and cognition: an understudied issue in women's health.J Psychosom Res. 2003; 54: 129-139Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Diabetes has also been associated with a greater prevalence of global impairment in cognition,8Kalmijn S. Feskens E.J.M. Launer L.J. Kromhout D. Hyperinsulemia, impaired glucose tolerance and cognitive function (the Zutphen Elderly Study).Diabetologica. 1995; 38: 1096-1102Crossref PubMed Scopus (234) Google Scholar as well as a higher incidence of cognitive decline9Gregg E.W. Yaffe K. Cauley J.A. Rolka D.B. Blackwell T.L. Venkat Narayan K.M. Cummings S.R. Is diabetes associated with cognitive impairment and cognitive decline among older women?.Arch Intern Med. 2000; 160: 174-180Crossref PubMed Scopus (437) Google Scholar in community-based studies. For example, data from the Cardiovascular Health Study (CHS) showed that compared with those who were normoglycemic, patients with diabetes or elevated levels of serum glucose were more likely to exhibit cognitive decline over the next 7 years of follow-up.10Haan M.N. Shemanski L. Jagust W.J. Manolio T.A. Kuller L. The role of APOE 4 in modulating effects of other risk factors for cognitive decline in elderly men.JAMA. 1999; 282: 40-46Crossref PubMed Scopus (390) Google Scholar In addition, recent studies have shown that diabetes is a risk factor for Alzheimer disease11Ott A. Stolk R.P. van Harskamp F. Pols H.A. Hofman A. Breteler M.M. Diabetes mellitus and the risk of dementia: the Rotterdam Study.Neurology. 1999; 53: 1937-1942Crossref PubMed Google Scholar, 12Leibson C.K. Rocca W.A. Hanson V.A. Cha R. Kokmen E. O'Brien P.C. Palumbo P.J. Risk of dementia among persons with diabetes mellitus: a population-based cohort study.Am J Epidemiol. 1997; 145: 301-308Crossref PubMed Scopus (542) Google Scholar and vascular dementia,13Curb J.D. Rodriguez B.L. Abbott R.D. Petrovitch H. Ross G.W. Masaka K.H. Foley D. Blanchette P.L. Harris T. Chen R. White L.R. Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance.Neurology. 1999; 52: 971-975Crossref PubMed Google Scholar the 2 most common forms of dementia. Furthermore, data suggest that patients with diabetes and hypertension are more likely to have prevalent cognitive impairment than those with diabetes or hypertension alone.14Elias P.K. Elias M.F. D'Agostino R.B. Cupples L.A. Wilson P.W. Silbershatz H. Wolf P.A. NIDDM and blood pressure as risk factors for poor cognitive performance: the Framingham study.Diabetes Care. 1997; 20: 1388-1395Crossref PubMed Scopus (306) Google Scholar More sensitive radiologic tools, such as magnetic resonance imaging (MRI), have enhanced the ability to detect changes in brain structure and function, providing new opportunities for evaluating brain anatomic correlates of cognitive changes. MRI studies within the past decade have shown that patients with diabetes have an increased risk for brain atrophy15Lunetta M. Damanti A.R. Fabbri G. Lombardo M. DiMauro M. Mughini L. Evidence by magnetic resonance imaging of cerebral alterations of atrophy type in young insulin-dependent diabetic patients.J Endocrinol Invest. 1994; 17: 241-245Crossref PubMed Scopus (69) Google Scholar and lacunar infarcts.16Longstreth Jr, W.T. Bernick C. Manolio T.A. Bryan N. Jungreis C.A. Price T.R. Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study.Arch Neurol. 1998; 55: 1217-1225Crossref PubMed Scopus (434) Google Scholar As with cognitive impairment, patients with diabetes and hypertension have been shown to be at greater risk for brain atrophy than those with none or only 1 of the risk factors.17Schmidt R. Launer L.J. Nilsson L.G. Pajak A. Sans S. Berger K. Breteler M.M. de Ridder M. Dufouil C. Fuhrer R. Giampaoli S. Hofman A. CASCADE ConsortiumMagnetic resonance imaging of the brain in diabetes: the Cardiovascular Determinants of Dementia (CASCADE) study.Diabetes. 2004; 53: 687-692Crossref PubMed Scopus (213) Google Scholar A number of mechanisms are proposed by which type 2 diabetes may increase the risk for cognitive impairment. Metabolic changes in the brain associated with diabetes may affect endothelial function, protein synthesis, DNA, mitochondrial function, and the degree of free radical and inflammatory response.18Hoyer S. Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis.J Neural Transm. 1998; 105: 415-422Crossref PubMed Scopus (217) Google Scholar, 19Sasaki N. Fukatsu R. Tsuzuki K. Hayashi Y. Yoshida T. Fujii N. Koike T. Wakayama I. Yanagihara R. Garruto R. Amano N. Makita Z. Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases.Am J Pathol. 1998; 153: 1149-1155Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar At the other extreme of the glycemic-control continuum, hypoglycemic events may have the potential for a significant adverse impact on brain metabolism, which is highly glucose dependent. Hypertension, a common comorbidity with type 2 diabetes, increases the risk for vascular and endothelial damage and is associated with cognitive impairment and brain lesions. Although theoretical considerations suggest that lipid-lowering therapy may have a role in maintaining neuronal viability,20DeKosky S.T. Statin therapy in the treatment of Alzheimer disease: what is the rationale?.Am J Med. 2005; 118: 48-53Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar the relation between hyperlipidemia and cognitive impairment remains unproved.21Zandi P.P. Sparks D.L. Khachaturian A.S. Tschanz J. Norton M. Steinberg M. Welsh-Bohmer K.A. Breitner J.C. Cache County Study InvestigatorsDo statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study.Arch Gen Psychiatry. 2005; 62: 217-224Crossref PubMed Scopus (300) Google Scholar The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is designed to test whether 3 complementary medical treatment strategies for type 2 diabetes reduce the very high rate of major cardiovascular disease morbidity and mortality in this disease. The treatment strategies tested in ACCORD are (1) intensive glycemic control, (2) treatment to increase high-density lipoprotein (HDL) cholesterol and lower triglycerides (in the context of good low-density lipoprotein [LDL] cholesterol and glycemic control), and (3) intensive treatment of systolic blood pressure (in the context of good glycemic control). The overall ACCORD trial design is a double 2 × 2 factorial design in 10,251 participants with type 2 diabetes, with all participants in the overarching glycemia trial. In addition, one 2 × 2 component of the trial addresses the lipid question in 5,518 participants, while the other 2 × 2 component addresses the blood pressure question in 4,733 participants.22ACCORD Study GroupAction to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods.Am J Cardiol. 2007; 99: 21i-33iPubMed Google Scholar Thus, the ACCORD trial provides a unique opportunity, in the context of a randomized clinical trial, to address further the relation between cognitive impairment and type 2 diabetes, associated risk factors, and their treatment. From within the overall ACCORD study population, a sample of 2,977 participants were recruited into the ACCORD Memory in Diabetes (ACCORD-MIND) substudy. ACCORD-MIND will seek to determine whether the intensity of diabetes treatment affects cognitive function and MRI-assessed brain structure. The collection of longitudinal cognitive data is planned on 3 occasions (at baseline and at 20 and 40 months) from the 2,977 participants, and the acquisition of 2 MRI brain scans (at baseline and at 40-month follow-up) is planned for 630 of these participants. Of 7 ACCORD clinical center networks (CCNs), which provide oversight of clinics in specific regions of the United States and Canada, 6 are participating in ACCORD-MIND. These 6 networks include 54 individual clinics that recruit and provide care to patients. Clinics located within 2 hours' driving time of 1 of the 4 MRI centers are participating in the MRI substudy. Participants eligible for ACCORD-MIND must have been randomized to glycemia control and to either the blood pressure arm or the lipid treatment arm in the overall ACCORD trial, as described elsewhere in this supplement.22ACCORD Study GroupAction to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods.Am J Cardiol. 2007; 99: 21i-33iPubMed Google Scholar Recruitment into, and consent for, ACCORD-MIND had to take place <45 days after randomization into the overall ACCORD trial. The collection of longitudinal cognitive data was planned in a minimum of 350 participants in each of the glycemia, lipid, and blood pressure cells of the ACCORD-MIND study (Table 1). Similarly, the MRI component of ACCORD-MIND (Table 2) planned the recruitment of 640 participants who received the cognitive evaluation. Recruitment into this component of MIND was initially confined to the blood pressure trial14Elias P.K. Elias M.F. D'Agostino R.B. Cupples L.A. Wilson P.W. Silbershatz H. Wolf P.A. NIDDM and blood pressure as risk factors for poor cognitive performance: the Framingham study.Diabetes Care. 1997; 20: 1388-1395Crossref PubMed Scopus (306) Google Scholar but was opened to participants in the lipid trial when MRI recruitment lagged. The effect of the glycemia intervention will be tested across the blood pressure and lipid trials.Table 1Study design for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Memory in Diabetes Study (ACCORD-MIND) cognition substudy: 6 centers (N = 2,977)⁎Targeted sample sizes are in parentheses.Lipid TrialBP TrialGlucose+Fibrate–active drug n = 383 (n = 350)Fibrate-placebo n = 381 (n = 350)BP+ n = 362 (n = 350)BP− n = 343 (n = 350)Glucose−Fibrate–active drug n = 399 (n = 350)Fibrate-placebo n = 375 (n = 350)BP+ n = 383 (n = 350)BP− n = 351 (n = 350)BP = blood pressure; + = intensive; – = standard Targeted sample sizes are in parentheses. Open table in a new tab Table 2Study design for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Memory in Diabetes Study (ACCORD-MIND) magnetic resonance imaging substudy: 4 centers (n = 630)⁎Targeted sample sizes are in parentheses.Lipid TrialBP TrialGlucose+Fibrate–active drug n = 53 (n = 60)Fibrate-placebo n = 59 (n = 60)BP+ n = 90 (n = 100)BP− n = 99 (n = 100)Glucose−Fibrate–active drug n = 62 (n = 60)Fibrate-placebo n = 64 (n = 60)BP+ n = 112 (n = 100)BP− n = 91 (n = 100)BP = blood pressure; + = intensive; – = standard. Targeted sample sizes are in parentheses. Open table in a new tab BP = blood pressure; + = intensive; – = standard BP = blood pressure; + = intensive; – = standard. The overall ACCORD inclusion criteria, in addition to the following criteria, are confirmed in all participants in the ACCORD-MIND study: (1) willingness to participate in the average 5-year follow-up of the ACCORD trial and this substudy, (2) age ≥55 years, (3) English or Spanish as the usual language (for testing purposes), and (4) informed consent provided. The exclusion criteria for ACCORD-MIND are similar to those for the overall ACCORD trial, including (1) diagnosis and treatment for cancer within the past 5 years that, in the judgment of clinical study staff members, would compromise a participant's ability to adhere to the protocol and complete the trial (exceptions could include nonmelanoma skin cancer and early-stage prostate cancer), and (2) any condition that, in the judgment of clinical study staff members, would preclude full participation in the study (eg, preexisting clinical evidence of dementia, substance abuse). Additional (MRI only) exclusion criteria are the following: (1) the presence of a pacemaker, cerebral aneurysm clips or other clips from previous brain surgery, metal fragments in the eyes, a neurostimulator, a Starr-Edwards heart valve (implanted before 1970), other metallic valves, severe head tremor or other problems resulting in a participant's being unable to lie supine, participant weight exceeding the limit set by the MRI manufacturer (150 kg), cochlear implants, participant size exceeding the gantry size limits, epidural catheters, or shunts with flow valves; and (2) known previous inability to complete an MRI scan because of claustrophobia. The ACCORD-MIND study is designed to test the primary hypothesis that, over a 40-month period, the rate of decline in cognitive function (as measured by the Digit Symbol Substitution Test [DSST] from the Wechsler Adult Intelligence Scale–Third Edition; Harcourt Assessment, Inc., San Antonio, TX)23Wechsler D. Wechsler Adult Intelligence Scale–Revised. Psychological Corporation, New York1988Google Scholar and total brain volume (on the basis of MRI) will be lower in the group randomized to intensive glycemic control (target glycosylated hemoglobin [HbA1c] <6.0%) compared with the group randomized to standard glycemic control (target HbA1c, 7.0%–7.9%; expected median HbA1c, 7.5%). In addition, several secondary hypotheses are addressed. Specifically, in the context of good glycemic control, over a 40-month period:•The rate of decline in cognitive function (as measured by the DSST) and MRI-based total brain volume will be lower in the group randomized to intensive blood pressure control (target systolic blood pressure <120 mm Hg) compared with the group randomized to standard blood pressure control (target systolic blood pressure <140 mm Hg).•The rate of decline in cognitive function (as measured by the DSST) will be lower in the group randomized to receive fibrate to increase HDL cholesterol and lower triglyceride levels compared with the group randomized to receive placebo (in a double-blind context), in the presence of equivalent 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy for the treatment of LDL cholesterol. Within the lipid trial, the MRI sample size will not be sufficient to address the effect of the lipid intervention on brain volume. Additional tertiary hypotheses will be tested in ACCORD-MIND. One hypothesis is that the ability to manage diabetes and adhere to the ACCORD protocol, as measured by a 4-item questionnaire, will be better in patients in the intensive glycemic intervention arm because of less decline in cognitive function compared with those in the standard-treatment arm. In addition, MRI data from ACCORD-MIND will be analyzed for the effects of treatment on specific regions of the brain, such as the hippocampus, and on the incidence and progression of regional and total brain abnormal white matter content. The already high participant and staff member burden within the main ACCORD trial, the large ACCORD-MIND sample size, and the multiple centers participating in ACCORD-MIND (n = 54) required that we design a focused cognitive battery targeted to the cognitive functions of interest, that it be easy to score, and that it could be administered within a 30-minute period. The test battery also had to be sensitive to early or mild cognitive changes that could affect daily functioning. Thus, the final ACCORD-MIND test battery was formulated to meet several objectives: (1) sensitivity to changes in memory and in information-processing speed and executive function, (2) standardization and good validation in the target age groups, (3) ease of administration, and (4) the availability of a comparable Spanish version. The test selection was based on a battery used previously as a part of a multicenter MRI study.24Launer L.J. Oudkerk M. Nilsson L.-G. Alperovitch A. Berger K. Breteler M.M.B. Fuhrer R. Giampaoli S. Nissinen A. Pajak A. et al.CASCADE: a European collaborative study on vascular determinants of brain lesions Study design and objectives.Neuroepidemiology. 2000; 19: 113-120Crossref PubMed Scopus (37) Google Scholar The primary cognitive outcome of ACCORD-MIND is the score on the DSST.23Wechsler D. Wechsler Adult Intelligence Scale–Revised. Psychological Corporation, New York1988Google Scholar An omnibus instrument, the DSST is designed primarily to measure psychomotor speed, but performance is also affected by memory and attention. Therefore, we expect it to be sensitive to the array of cognitive changes previously shown to be affected by diabetes. In addition, many clinical and epidemiologic studies have used the test because it has a wide distribution of scores in the target population, avoiding ceiling or floor effects. Secondary cognitive outcomes will incorporate data from of all the tests (see later) and include analyses of composite scores for memory and executive function. Executive function includes skills necessary for complex, goal-directed behavior and adaptation to environmental conditions. Table 3 lists the composition of the cognitive test battery. In addition to the DSST, the battery includes a brief self-report questionnaire (4 questions) on cognitive ability to manage diabetes, the Mini-Mental State Examination (MMSE) (Psychological Assessment Resources, Inc., Lutz, FL),25Folstein M.F. Folstein S.E. McHugh P.R. "Mini-mental state": a practical method for grading the cognitive state of patients for the clinician.J Psychiatr Res. 1975; 12: 189-198Abstract Full Text PDF PubMed Scopus (69806) Google Scholar the Rey Auditory Verbal Learning Test (RAVLT),26Lezak M.D. Neuropsychological Assessment. 3rd ed. Oxford University Press, New York1995Google Scholar the Stroop test,27Stroop J.R. Studies of interference in serial verbal reactions.J Exp Psychol. 1935; 18: 643-662Crossref Scopus (12232) Google Scholar, 28Houx P.J. Jolles J. Vreeling F.W. Stroop interference: aging effects assessed with the Stroop color-word test.Exp Aging Res. 1993; 19: 209-224Crossref PubMed Scopus (294) Google Scholar and a measure of depression, the Patient Health Questionnaire (PHQ) (Pfizer Inc, New York, NY).29Kroenke K. Spitzer R.L. Williams H.B.W. The PHQ-9: validity of a brief depression severity measure.J Gen Intern Med. 2001; 16: 606-613Crossref PubMed Scopus (19891) Google ScholarTable 3The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Memory in Diabetes Study (ACCORD-MIND) test battery and order of administrationDomainTime (min)Usual LanguageOutcome ScoreEnglishSpanishGlobal mental status5MMSEMMSE (Spanish version)Total scoreMemory I7RAVLTSpanish English Verbal Learning TestTotal no. of words recalledPsychomotor speed2DSSTSymbol-DigitNo. of correct entriesExecutive function7Stroop testStroop test (Spanish version)Time to completeDepression3PHQPHQTotal scoreMemory II4RAVLT–Delayed RecallSpanish English Verbal Learning TestTotal no. of words recalledDSST = Digit Symbol Substitution Test (from the Wechsler Adult Intelligence Scale–Third Edition; Harcourt Assessment, Inc., San Antonio, TX); MMSE = Mini-Mental State Examination (Psychological Assessment Resources, Inc., Lutz, FL); PHQ = Patient Health Questionnaire (Pfizer, Inc., New York, NY); RAVLT = Rey Auditory Verbal Learning Test. Open table in a new tab DSST = Digit Symbol Substitution Test (from the Wechsler Adult Intelligence Scale–Third Edition; Harcourt Assessment, Inc., San Antonio, TX); MMSE = Mini-Mental State Examination (Psychological Assessment Resources, Inc., Lutz, FL); PHQ = Patient Health Questionnaire (Pfizer, Inc., New York, NY); RAVLT = Rey Auditory Verbal Learning Test. Global mental status is assessed by the 30-point MMSE. This measure, administered in about 5 minutes, has been shown to have adequate sensitivity for moderate cognitive changes. Because many studies use this instrument, we will be able to compare the levels of ACCORD-MIND participants with those of other samples.30Shumaker S.A. Reboussin B.A. Espeland M.A. Rapp S.A. McBee W.L. Dailey M. Bowen D. Terell T. Jones B.J. The Women's Health Initiative Memory Study (WHIMS): a trial of the effect of estrogen therapy in preventing and slowing the progression of dementia.Control Clin Trials. 1998; 19: 604-621Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar, 31Resnick S.M. Coker L.H. Maki P.M. Rapp S.R. Espeland M.A. Shumaker S.A. The Women's Health Initiative Study of Cognitive Aging (WHISCA): a randomized clinical trial of the effects of hormone therapy on age-associated cognitive decline.Clin Trials. 2004; 1: 440-450Crossref PubMed Scopus (88) Google Scholar Verbal memory is evaluated using the RAVLT (English) and the Spanish English Verbal Learning Test (SEVLT). The study participant is read a list of 15 words 5 times. After each time the list is given, the participant is asked to immediately recall as many words as possible. After the fifth recall, an interference list is presented, after which the participant is asked to spontaneously recall words from the original list. After a 10-minute interval has passed, the participant is asked again to remember as many words as possible from the list (with a 7-minute time limit).26Lezak M.D. Neuropsychological Assessment. 3rd ed. Oxford University Press, New York1995Google Scholar The DSST is a symbol substitution task in which a key is presented at the top of a page showing the numbers 1–9, with each number paired with a different symbol. Below the key are paired rows of blank squares with randomly assigned displayed numbers (1–9) printed in the upper square and a blank square below each number. As rapidly as possible, the participant fills in the blanks with the symbols that correspond to the numbers in the key. The score is the total number of correctly entered symbols completed in 2 minutes.23Wechsler D. Wechsler Adult Intelligence Scale–Revised. Psychological Corporation, New York1988Google Scholar The Stroop test evaluates the ability to view complex visual stimuli and to respond to one stimulus dimension while suppressing response to another competitive stimulation. The study participant first reads aloud words denoting colors printed in black ink, then names aloud colored bars, and finally has to read aloud words denoting colors, each of which is printed in an incongruent color ink (eg, "blue" in red letters). In this modified version, 40 words and bars are used. The amount of time for the participant to perform the readings and the number of errors are recorded. A limit of 120 seconds is set for subtests I and II and 180 seconds for subtest III.27Stroop J.R. Studies of interference in serial verbal reactions.J Exp Psychol. 1935; 18: 643-662Crossref Scopus (12232) Google Scholar, 28Houx P.J. Jolles J. Vreeling F.W. Stroop interference: aging effects assessed with the Stroop color-word test.Exp Aging Res. 1993; 19: 209-224Crossref PubMed Scopus (294) Google Scholar Depression is an important covariate of cognitive function. The PHQ,29Kroenke K. Spitzer R.L. Williams H.B.W. The PHQ-9: validity of a brief depression severity measure.J Gen Intern Med. 2001; 16: 606-613Crossref PubMed Scopus (19891) Google Scholar a simple instrument that is sensitive to specific symptoms of depression in older subjects, is administered during the prescribed 10-minute interval between the Stroop and RAVLT delayed-recall tests. Finally, all participants will be administered 4 questions designed to assess self-reported ability to manage therapy for diabetes. These questions address areas such as difficulty remembering to monitor glucose and taking medication at the prescribed time. The maintenance of quality control for the cognitive assessment portion of the protocol is ensured through training, certification, and monitoring. A 1-day training session on the ACCORD-MIND cognitive battery was provided at each of the network sites by the ACCORD-MIND Coordinating Center. Training included a presentation on each test in the cognitive battery, detailed instruction on the administration and scoring of each test, discussion of challenges to data fidelity, direct observation of the ACCORD-MIND battery test administration, and practice test administrations with feedback. All trainees were certified for administration of the ACCORD-MIND battery by direct observation or submitting to the Coordinating Center an audiotape of th
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