higher cortisol levels after 1.5 mg dexa- methasone administration, was related to declarative memory impairments, possi- bly reﬂecting hippocampal dysfunction, in 30 individuals with type 2 diabetes compared with age-, sex-, and education- matched control subjects (18). However, the association between cortisol and cog- nitive function disappeared after adjust- ment for glycemic control (A1C). The same investigators reported similarly im- paired HPA axis feedback control in asso- ciation with verbal declarative memory deﬁcits in 41 subjects with type 2 diabetes (1). In the latter study, the subjects with type 2 diabetes also had reduced hip- pocampal and prefrontal volumes, but there were no signiﬁcant associations be- tween the cortisol measurements and magnetic resonance image ﬁndings (1). Despite these ﬁndings from animal and human studies, information from large-scale epidemiological studies of rep- resentative populations is lacking, which could conﬁrm or refute an association be- tween circulating plasma cortisol levels and age-related cognitive impairment. We therefore examined the relationship between fasting cortisol and both late-life cognitive ability and estimated lifetime cognitive change in a large, representative study population of people with type 2 diabetes (the Edinburgh Type 2 Diabetes Study [ET2DS]). The ET2DS has the ad- vantage over many previous epidemiolog- ical studies of having detailed cognitive testing in a range of cognitive domains and very extensive phenotyping for po- tential confounding or mediating factors. RESEARCH DESIGN AND METHODS — This report on the study cohort is based upon the cross-sectional phase of the ET2DS, an epidemiological study investigating mechanisms and risk factors for diabetes-related cognitive de- cline and for the development and pro- gression of micro- and macrovascular disease in diabetes (19). Participants in the ET2DS, aged 60 –75 years, were re- cruited at random from a comprehensive database of all subjects with established type 2 diabetes, living in the Lothian area of central Scotland between August 2006 and August 2007. Recruitment and exam- ination of the study cohort has been de- scribed in detail previously (19). Ethical approval was obtained from the local re- search ethics committee, and all subjects gave written, informed consent. Subjects taking glucocorticoid therapy by any route within the last 3 months (n 147) care.diabetesjournals.org were also excluded from the current anal- ysis, leaving a sample size of 919. Clinical protocol Brieﬂy, subjects attended a local research clinic after an overnight fast. A fasting ve- nous blood sample was taken between 0800 h and 0830 h, for measurement of cortisol and other biochemical parame- ters. Subjects completed questionnaires describing baseline demographics and underwent detailed physical examination and cognitive testing. Subjects completed a self-adminis- tered questionnaire, including validated questions on education (highest level at- tained); a medical diagnosis of myocardial infarction, stroke, or angina; duration of diabetes; smoking; frequency of alcohol consumption over the last year; and the World Health Organization chest pain questionnaire. Height, weight, brachial blood pressure, and posterior tibial and dorsalis pedis systolic pressures (for cal- culation of the ankle-brachial index [ABI]) were measured and an electrocar- diogram was (ECG) recorded. Data were collected from the information and statis- tics division of the National Health Ser- vice Scotland on all medical and surgical discharges from Scottish hospitals since 1981 (SMR01 scheme). Any ICD-10 or ICD-9 codes for cardiovascular or cere- brovascular disease were extracted and used together with self-reported vascular disease and ﬁndings from the chest pain questionnaire and ECG (in addition to a review of clinical notes where required) to deﬁne myocardial infarction, angina, and stroke, according to predeﬁned criteria. Cognitive assessment Cognitive ability was assessed on the same morning as the blood sampling and physical examination, after subjects had eaten a snack and blood glucose was con- ﬁrmed as 4 mmol/l, using a battery of psychometric tests, providing a compre- hensive and validated assessment of cog- nitive function and mood state (19). These included tests of nonverbal mem- ory and immediate and delayed verbal memory (faces and family pictures subtest [FACES]), logical memory (LM) (from the Wechsler Memory Scale III U.K.), work- ing memory, nonverbal reasoning, pro- cessing speed (letter-number sequencing [LNS]), matrix reasoning (MR), digit sym- bol test (DST) (from the WAIS III U.K.), executive function (verbal ﬂuency test [VFT]), and mental ﬂexibility (trail- making test, part B [TMT]). A test of vo- Reynolds and Associates cabulary (typically used to assess “crystallized” intelligence) was also in- cluded, using the combined Junior and Senior Mill Hill Vocabulary Scale (MHVS) synonyms (19). As results on vocabulary tests such as the MHVS vary little with aging, they are used to approximate peak prior cognitive ability. Subjects were also assessed using the Hospital Anxiety and Depression Scale (HADS), since mood can affect cognitive test results. Laboratory analysis Plasma cortisol levels were measured by radioimmunoassay (MP Biomedicals, Cambridge, U.K.) with intra-assay coefﬁ- cient of variation (CV) 5.1–7.0% and in- terassay CV 6.0 –7.9%. Statistical analysis Data were analyzed using SPSS version 15.0. As the distribution of TMT scores was skewed, we used natural log to trans- form TMT scores (lnTMT). Scores from the seven cognitive tests were used to test for the presence of a general cognitive abil- ity factor, g, via a principal-components analysis. Scree slope analysis indicated that there was only a single principal com- ponent, which accounted for 44.0% of the total test variance. Each individual test loaded strongly on the ﬁrst unrotated principal component (g; range 0.454 – 0.794); only the loading for the TMT was negative ( 0.794) due to a high score on this test reﬂecting lower cognitive ability. To examine associations between cor- tisol levels and current cognitive ability, linear regression was used to assess the association between cortisol and unad- justed cognitive test scores and then age- and sex-adjusted cognitive test scores. To examine associations between cortisol levels and estimated lifetime cognitive change, linear regression was used with additional adjustment for MHVS. A fur- ther model also included adjustment for additional covariates to control for mood (HADS score), duration of diabetes and glycemic control (A1C), cardiovascular risk factors (total cholesterol, BMI, hyper- tension, smoking, and alcohol intake), cardiovascular disease (myocardial in- farction, angina, stroke, ABI), and level of education. Finally, we tested all the inter- action terms between cortisol and all the variables included in the regression anal- ysis. Signiﬁcant interaction terms were entered into a further regression model. DIABETES CARE, VOLUME 33, NUMBER 4, APRIL 2010 715