the et2ds is a sample of men and women aged 6075 years with type 2 diabetes .
the subjects were randomly selected by sex and 5-year age bands from the comprehensive lothian diabetes register ( ldr ) of people with type 2 diabetes living in lothian , scotland .
a sample size of 1,000 was targeted to detect associations between baseline risk factors and both cognitive ability at baseline and cognitive change during subsequent follow - up .
exclusion criteria , applied at the time of physical examination , have been reported previously ( 5 ) .
all subjects provided written informed consent , and the study was approved by the lothian research ethics committee .
physical examinations were performed between august 2006 and august 2007 by trained researchers using standard operating procedures ( 5 ) .
a fasting venous blood sample was taken for measurement of inflammatory markers , total serum cholesterol , and plasma a1c .
following measurements of height and weight , a 12-lead electrocardiogram ( ecg ) was taken for subsequent minnesota coding ( http://www.epi.umn.edu/ecg/ ) .
after a 10-min rest in the supine position , systolic and diastolic blood pressure was measured in the right arm using a standard stethoscope and aneroid dial sphygmomanometer .
right and left brachial , posterior tibial , and dorsalis pedis systolic pressures were then taken using an aneroid sphygmomanometer and a doppler probe .
a self - administered questionnaire included questions on education ; history of myocardial infarction ( mi ) , stroke or angina ; year of diabetes diagnosis ; smoking ; current medications ; and the world health organization ( who ) chest pain questionnaire ( 6 ) .
data were collected from the information and services division of the national health service ( nhs ) health services scotland on all medical and surgical discharges from scottish hospitals since 1981 ( scottish morbidity record [ smr01 ] scheme ) , and any icd-10 codes ( or the equivalent icd-9 codes ) indicating cardiovascular or cerebrovascular disease were extracted .
fluid cognitive ability was assessed using tests of : nonverbal memory and immediate and delayed verbal declarative memory ( faces and family pictures subtest , logical memory subtest from the wechsler memory scale iii ) ; working memory , nonverbal reasoning , and processing speed ( letter number sequencing , matrix reasoning , digit symbol test from the wechsler adult intelligence scale - iii [ wais iii ] ) ; executive function ( verbal fluency test ) ; and mental flexibility ( trail making test 
vocabulary ( crystallized intelligence ) was measured using the combined junior and senior mill hill vocabulary scale ( mhvs ) synonyms ( 12 ) .
as results on vocabulary - based tests vary little with ageing , they can be used to approximate peak prior cognitive ability ( 13 ) .
late - life cognition adjusted for vocabulary also correlates highly with actual cognitive change ( 14 ) . the hospital anxiety and depression scale ( 15 )
blood samples were processed at the research clinic , and plasma was stored at 40c .
assays for plasma crp , il-6 , and tnf- were performed in the university department of medicine , glasgow royal infirmary .
tnf- and il-6 antigen levels were determined using high - sensitivity elisa kits ( r&d systems , oxon , u.k . ) .
errors identified by comparing the double data entries were resolved by referring to the paper records .
anonymized data on demographic and clinical variables from the ldr were used to compare the characteristics of study responders and nonresponders .
ankle brachial index , a measure of subclinical atherosclerosis ( 17 ) , was calculated by dividing the lowest of the ankle pressures by the higher of the arm pressures .
smoking was categorized as current , ex , or never - smoked , with anyone stopping within the past 6 months recategorized as a current smoker .
duration of diabetes was calculated to the nearest year by subtracting the self - reported year of diagnosis from the date of attendance at the research clinic .
the highest self - reported level of education was categorized as primary , secondary , professional qualification , or university / college degree .
scottish index of multiple deprivation ( deprivation ) ( 18 ) was assigned to each subject according to their postcode of residence .
the following criteria were used to define mi : 1 ) subject recall of a doctor 's diagnosis of mi , 2 ) positive who chest pain questionnaire for mi , 3 ) ecg evidence of ischemia ( minnesota codes 1.11.3 , 4.14.2 , 5.15.3 or 7.1 ) , and 4 ) prior hospital discharge code for mi ( icd-10 codes i21i23 , i252 ) .
mi was recorded if two of the first three criteria were met or if both the first and last criteria were met .
equivalent criteria for angina were : 1 ) subject recall of a doctor 's diagnosis of the condition or being on regular medication for angina , 2 ) positive who chest pain questionnaire for angina , 3 ) ecg evidence of ischemia , and 4 ) prior hospital discharge code for ischemic heart disease ( icd-10 codes i20i25 ) .
angina was recorded if two of the first three criteria were met or if both the first and last criteria were met .
stroke was recorded if two of three of the following criteria were met : 1 ) subject recall of a doctor 's diagnosis of stroke , 2 ) prior hospital discharge code consistent with stroke ( icd-10 codes i61 , i63i66 , i679 , i694 ) , and 3 ) confirmation by review of clinical notes that the event was not due to a transient ischemic attack .
continuous variables were normally distributed apart from trail making test scores , crp , il-6 , and tnf- levels , which were transformed using natural logarithms .
the inflammatory markers were trimmed for points exceeding 3.5 sds from the mean prior to analysis .
scores from the fluid cognitive tests were used to obtain a general cognitive ability factor ( g ) via principal components analysis .
age- and sex - adjusted linear regression assessed the association between cognitive scores and inflammatory markers .
further adjustments were made for vocabulary ( mhvs ) and then for additional covariates to adjust for mood ( hospital anxiety and depression scale depression score ) , duration of diabetes , glycemic control ( plasma a1c ) , cardiovascular risk factors ( total cholesterol , bmi , diastolic blood pressure , smoking ) , cardiovascular disease ( mi , angina , stroke , ankle brachial index ) , and level of education . the analyses had over 90% power for a two - sided significance test (  = 0.05 ) to detect a standardized  coefficient of 0.10 .
physical examinations were performed between august 2006 and august 2007 by trained researchers using standard operating procedures ( 5 ) .
a fasting venous blood sample was taken for measurement of inflammatory markers , total serum cholesterol , and plasma a1c . following measurements of height and weight , a 12-lead electrocardiogram ( ecg )
after a 10-min rest in the supine position , systolic and diastolic blood pressure was measured in the right arm using a standard stethoscope and aneroid dial sphygmomanometer .
right and left brachial , posterior tibial , and dorsalis pedis systolic pressures were then taken using an aneroid sphygmomanometer and a doppler probe .
a self - administered questionnaire included questions on education ; history of myocardial infarction ( mi ) , stroke or angina ; year of diabetes diagnosis ; smoking ; current medications ; and the world health organization ( who ) chest pain questionnaire ( 6 ) .
data were collected from the information and services division of the national health service ( nhs ) health services scotland on all medical and surgical discharges from scottish hospitals since 1981 ( scottish morbidity record [ smr01 ] scheme ) , and any icd-10 codes ( or the equivalent icd-9 codes ) indicating cardiovascular or cerebrovascular disease were extracted .
fluid cognitive ability was assessed using tests of : nonverbal memory and immediate and delayed verbal declarative memory ( faces and family pictures subtest , logical memory subtest from the wechsler memory scale iii ) ; working memory , nonverbal reasoning , and processing speed ( letter number sequencing , matrix reasoning , digit symbol test from the wechsler adult intelligence scale - iii [ wais iii ] ) ; executive function ( verbal fluency test ) ; and mental flexibility ( trail making test  part b ) .
vocabulary ( crystallized intelligence ) was measured using the combined junior and senior mill hill vocabulary scale ( mhvs ) synonyms ( 12 ) .
as results on vocabulary - based tests vary little with ageing , they can be used to approximate peak prior cognitive ability ( 13 ) .
late - life cognition adjusted for vocabulary also correlates highly with actual cognitive change ( 14 ) . the hospital anxiety and depression scale ( 15 )
blood samples were processed at the research clinic , and plasma was stored at 40c .
assays for plasma crp , il-6 , and tnf- were performed in the university department of medicine , glasgow royal infirmary .
tnf- and il-6 antigen levels were determined using high - sensitivity elisa kits ( r&d systems , oxon , u.k . ) .
errors identified by comparing the double data entries were resolved by referring to the paper records .
anonymized data on demographic and clinical variables from the ldr were used to compare the characteristics of study responders and nonresponders .
ankle brachial index , a measure of subclinical atherosclerosis ( 17 ) , was calculated by dividing the lowest of the ankle pressures by the higher of the arm pressures .
smoking was categorized as current , ex , or never - smoked , with anyone stopping within the past 6 months recategorized as a current smoker .
duration of diabetes was calculated to the nearest year by subtracting the self - reported year of diagnosis from the date of attendance at the research clinic .
the highest self - reported level of education was categorized as primary , secondary , professional qualification , or university / college degree .
scottish index of multiple deprivation ( deprivation ) ( 18 ) was assigned to each subject according to their postcode of residence .
the following criteria were used to define mi : 1 ) subject recall of a doctor 's diagnosis of mi , 2 ) positive who chest pain questionnaire for mi , 3 ) ecg evidence of ischemia ( minnesota codes 1.11.3 , 4.14.2 , 5.15.3 or 7.1 ) , and 4 ) prior hospital discharge code for mi ( icd-10 codes i21i23 , i252 ) .
mi was recorded if two of the first three criteria were met or if both the first and last criteria were met .
equivalent criteria for angina were : 1 ) subject recall of a doctor 's diagnosis of the condition or being on regular medication for angina , 2 ) positive who chest pain questionnaire for angina , 3 ) ecg evidence of ischemia , and 4 ) prior hospital discharge code for ischemic heart disease ( icd-10 codes i20i25 ) .
angina was recorded if two of the first three criteria were met or if both the first and last criteria were met .
stroke was recorded if two of three of the following criteria were met : 1 ) subject recall of a doctor 's diagnosis of stroke , 2 ) prior hospital discharge code consistent with stroke ( icd-10 codes i61 , i63i66 , i679 , i694 ) , and 3 ) confirmation by review of clinical notes that the event was not due to a transient ischemic attack .
continuous variables were normally distributed apart from trail making test scores , crp , il-6 , and tnf- levels , which were transformed using natural logarithms .
the inflammatory markers were trimmed for points exceeding 3.5 sds from the mean prior to analysis .
scores from the fluid cognitive tests were used to obtain a general cognitive ability factor ( g ) via principal components analysis .
age- and sex - adjusted linear regression assessed the association between cognitive scores and inflammatory markers .
further adjustments were made for vocabulary ( mhvs ) and then for additional covariates to adjust for mood ( hospital anxiety and depression scale depression score ) , duration of diabetes , glycemic control ( plasma a1c ) , cardiovascular risk factors ( total cholesterol , bmi , diastolic blood pressure , smoking ) , cardiovascular disease ( mi , angina , stroke , ankle brachial index ) , and level of education . the analyses had over 90% power for a two - sided significance test (  = 0.05 ) to detect a standardized  coefficient of 0.10 .
from 5,454 invitations sent out , 1,252 people initially agreed to participate in the study and 1,066 ( 85% ) were recruited .
crude response rates varied between sex and 5-year age bands , from 13.6% in the oldest women aged 7074 years , to 27.5% in men aged 6569 years .
study participants were found to be similar to the 4,388 nonresponders ( table 1 ) . despite some statistically significant differences in demographic and clinical characteristics ,
similarities persisted when comparison was made by sex and 5-year age band and when adjustment was made for error rates in ldr data recording ( data not shown ) .
characteristics and clinical features of the et2ds population and nonresponders data are means  sd or n ( % ) .
* two subjects on the ldr had no data and were discarded from the analyses ( i.e. , total number of nonresponders was 4,388 ) ;  p < 0.001 (  test for independence or t test for differences between groups ) .
bp , blood pressure ; simd , scottish index of multiple deprivation . characteristics and clinical features of the et2ds population data are means  sd , median ( quartile range ) , or n ( % ) .
bp , blood pressure ; chd , coronary heart disease ( mi or angina ) ; dst , digit symbol test ; faces , faces and family pictures subtest ; hads , hospital anxiety and depression scale ; lm , logical memory ; lns , letter - number sequencing ; mr , matrix reasoning ; tmt , trail making test - part b ; vft , verbal fluency test . age- and sex - adjusted associations between inflammatory marker levels and cognitive test scores are shown in table 3 .
the associations for il-6 and tnf- were larger and statistically significant for the majority of the tests with standardized coefficients ranging from 0.074 to 0.173 ( all p < 0.05 ) .
multivariate associations between biomarkers and late - life cognition , and estimated cognitive change adjustment variables are hospital anxiety and depression scale depression score , duration of diabetes , a1c , total cholesterol , bmi , diastolic blood pressure , smoking , coronary heart disease ( mi or angina ) , stroke , ankle - brachial index , and level of education .
dst , digit symbol test ; faces , faces and family pictures subtest ; lm , logical memory ; lns , letter - number sequencing ; mr , matrix reasoning ; tmt , trail making test - part b ; vft , verbal fluency test .
all inflammatory measures associated with age- and sex - adjusted mhvs scores with standardized coefficients were : crp 0.075 ( p < 0.05 ) , il-6 0.091 ( p < 0.01 ) , and tnf- 0.087 ( p < 0.05 ) .
age , sex , and vocabulary adjustment weakened the magnitude and statistical significance of the associations ( table 3 ) .
however , the strongest il-6 and tnf- associations were retained after adjustments for both vocabulary and the other covariates .
this was particularly evident for il-6 with standardized coefficients for the full models in the ranges 0.074 to 0.113 .
in this representative population of people with type 2 diabetes , elevated levels of plasma crp , il-6 , and tnf- were significantly associated with poorer age- and sex - adjusted general cognitive abilities .
the maximum effect size for the age- and sex - adjusted g associations was with il-6 , which corresponded to a 0.173 decrease in g for every twofold increase in il-6 levels .
adjustments for cardiovascular disease / risk factors , glycemic control , duration of diabetes , and education resulted in reductions to the effect sizes .
however , this does not indicate whether these factors are confounders or whether they could be mediators in the same pathway leading to cognitive decline .
the association between il-6 and g , although weakened , remained statistically significant after full multivariate adjustment , suggesting a possible role for il-6 in cognitive decline .
analyses were repeated to exclude potential dementia cases ( mini mental state examination score < 24 , n = 33 ) , but this did not affect the results .
a limited number of high - quality studies have investigated the relationship between inflammatory biomarkers and cognition in nondiabetic populations .
these studies have found associations of a modest but similar order to those reported in the present study ( 2024 ) . as all our study participants had diabetes , we were not able to formally test for a differential effect size in diabetes .
the strengths of the present study include the application of a cognitive test battery covering major cognitive domains and extensive phenotyping for potential confounding or mediating factors .
the use of a general cognitive factor ( g ) helped avoid potential problems caused by multiple testing .
the study population had a verified clinical diagnosis of type 2 diabetes and was shown to be representative of the target population of elderly , community - dwelling men and women with the full spectrum of severity of type 2 diabetes ( from diet - controlled to insulin - treated ) .
although cross - sectional , the present results provide the best epidemiological evidence to date for an inflammation - cognition relationship in people with type 2 diabetes . as markers of inflammation
are sensitive to acute illness and alter with age , it is questionable whether a single , late - life measurement accurately reflects the lifetime risk of exposure to inflammation ( 25 ) .
this will be addressed in follow - up phases of the et2ds , when inflammatory markers and cognition will be remeasured and genetic predictors of inflammatory markers will be studied . in conclusion , raised circulating inflammatory marker levels are associated with poorer late - life cognitive ability in people with type 2 diabetes , even after adjustment for a vocabulary - based estimate of peak prior cognitive ability .
future longitudinal studies are required to confirm the direction of the association and whether there is evidence for causality .
 objectiveto determine whether circulating levels of the inflammatory markers c - reactive protein ( crp ) , interleukin ( il)-6 , and tumor necrosis factor ( tnf)- are associated with cognitive ability and estimated lifetime cognitive decline in an elderly population with type 2 diabetes.research design and methodsa cross - sectional study of 1,066 men and women aged 6075 years with type 2 diabetes and living in lothian , scotland ( the edinburgh type 2 diabetes study ) , was performed . 
 seven cognitive tests were used to measure abilities in memory , nonverbal reasoning , information processing speed , executive function , and mental flexibility . 
 the results were used to derive a general intelligence factor ( g ) . a vocabulary  based test was administered as an estimate of peak prior cognitive ability . 
 results on the cognitive tests were assessed for statistical association with inflammatory markers measured in a venous blood sample at the time of cognitive testing.resultshigher il-6 and tnf- levels were associated with poorer age- and sex - adjusted scores on the majority of the individual cognitive tests . 
 they were also associated with g using standardized regression coefficients 0.074 to 0.173 ( p < 0.05 ) . after adjusting for vocabulary , education level , cardiovascular dysfunction , duration of diabetes , and glycemic control , il-6 remained associated with three of the cognitive tests and with g.conclusionsin this representative population of people with type 2 diabetes , elevated circulating levels of inflammatory markers were associated with poorer cognitive ability . 
 il-6 levels were also associated with estimated lifetime cognitive decline . 
RESEARCH DESIGN AND METHODS
Clinical assessment.
Cognitive assessment.
Measurement of inflammatory markers.
Data analysis.
RESULTS
DISCUSSION