modest cognitive dysfunction is consistently reported in children and young adults with type 1 diabetes ( t1d ) ( 1 ) .
mental efficiency , psychomotor speed , executive functioning , and intelligence quotient appear to be most affected ( 2 ) ; studies report effect sizes between 0.2 and 0.5 ( small to modest ) in children and adolescents ( 3 ) and between 0.4 and 0.8 ( modest to large ) in adults ( 2 ) . whether effect sizes continue to increase as those with t1d age
a key issue not yet addressed is whether aging individuals with t1d have an increased risk of manifesting  clinically relevant cognitive impairment ,  defined by comparing individual cognitive test scores to demographically appropriate normative means , as opposed to the more commonly investigated  cognitive dysfunction ,  or between - group differences in cognitive test scores . unlike the extensive literature examining cognitive impairment in type 2 diabetes , we know of only one prior study examining cognitive impairment in t1d ( 4 ) .
this early study reported a higher rate of clinically relevant cognitive impairment among children ( 1018 years of age ) diagnosed before compared with after age 6 years ( 24% vs. 6% , respectively ) or a non - t1d cohort ( 6% ) .
cognitive impairment is important to study in an aging t1d population because these individuals are concurrently exposed to the consequences of long - term t1d and the negative effects of advancing age on cognition .
furthermore , several risk factors for age - related cognitive impairment , such as hypertension ( 5 ) and impaired renal function ( 6 ) , are highly prevalent in t1d , yet the contribution of these factors to worsening cognitive function in an aging t1d cohort remains unknown . characterizing cognitive impairment in aging participants with t1d is warranted based on findings from cognitive studies of aging populations without t1d : cognitive impairment is related to poor self - care ( 7 ) , high costs ( 8) , and disability ( 9 ) .
this study tests the hypothesis that childhood - onset t1d is associated with an increased risk of developing clinically relevant cognitive impairment detectable by middle age .
we compared cognitive test results between adults with and without t1d and used demographically appropriate published norms ( 1012 ) to determine whether participants met criteria for impairment for each test ; aging and dementia studies have selected a score 1.5 sd worse than the norm on that test , corresponding to performance at or below the seventh percentile ( 13 ) .
we also assessed relationships between t1d - specific variables and cognitive impairment ; based on the diabetes control and complications trial ( dcct)/epidemiology of diabetes interventions and complications ( edic ) study s 18-year cognitive follow - up results , we hypothesized that cognitive impairment would be associated with smoking history , high blood pressure , prevalent microvascular complications , and poor metabolic control ( 14 ) .
middle - aged adults with t1d ( n = 97 ; mean age and duration of diabetes 49 and 41 years , respectively ) were recruited from the pittsburgh epidemiology of diabetes complications ( edc ) study , an ongoing prospective study of individuals diagnosed before age 18 years and listed in the children s hospital of pittsburgh s diabetes registry .
the first edc clinical assessment occurred in 19861988 ( n = 658 ; mean age and duration of diabetes 28 and 19 years , respectively ) .
biennial physical exams and questionnaires occurred through 19961998 , with an additional exam in 20042006 ( for details see ref .
all locally dwelling edc participants as of 1 january 2010 ( n = 263 ) were invited to participate in an ancillary neuroimaging / neurocognitive study . of those ,
81 refused , 26 never responded , and 2 were lost to follow - up . of the 154 interested , 37 were ineligible for mri ( e.g. , metallic implants , claustrophobic ) and 5 had scheduling conflicts , leaving 112 eligible and scheduled for neuroimaging / neurocognitive testing .
of these , three failed to show for their scheduled visit . on their scheduled testing date ,
another three refused the mri and nine refused the cognitive test battery , yielding an analytic sample of n = 97 ( supplementary fig .
adults without t1d who were participating in an observational study of the effects of prehypertension ( blood pressure higher than  normal  but not high enough to qualify as hypertensive ) on cerebral structure and function served as a comparison group .
inclusion criteria were age 3560 years , local to pittsburgh , and blood pressure within the values of 120139/8089 mmhg .
of the 414 who responded to the mailing / advertisement and were screened to participate , 110 were ineligible for mri , 60 changed their mind , and 14 withdrew , leaving 230 enrolled ( mean age 46 years ) . to mirror the edc s primarily caucasian racial distribution ,
only caucasian participants with complete neuroimaging / neurocognitive data as of august 2013 ( n = 138 ) were included .
all study procedures received local institutional review board approval , and all participants provided informed consent before any research procedures were initiated . for all participants , blood pressure , bmi , and serum glucose
participants with serum glucose 70 mg / dl were given a snack then retested after 15 min ; no cognitive testing was performed if serum glucose was 70 mg / dl . weekly caloric expenditure ( kcal )
metabolic control and blood pressure were assessed biennially from baseline through 19961998 , again in 20042006 , and at the time of neurocognitive testing ( 20102013 ) ; this allowed calculations of long - term average blood pressure and glycemic control ( hba1c and  a1c months ,  a calculated measure assessing the degree and duration of hyperglycemia [ for details see ref .
16 ] ) . in 19901992 , arterial health was assessed via the ankle - brachial index ( abi ) ; two readings were averaged , then dichotomized as < 1.3 or > 1.3/noncompressible .
an abi > 1.3 is correlated with medial arterial calcification ( 17 ) , which is associated with arterial stiffening ( 18 ) .
prevalence of t1d complications ( nephropathy , coronary artery disease , distal symmetric polyneuropathy , cardiac autonomic neuropathy , retinopathy ) was assessed biennially from baseline through 19961998 , then again in 20042006 , using highly standardized methods ( for details see ref .
cognitive measures included estimated verbal intelligence ( north american adult reading test [ naart ] ) ; psychomotor efficiency ( digit symbol substitution test [ dsst ] and grooved pegboard [ gp ] ) ; executive function ( trail making test , part b [ tmtb ] , verbal fluency [ vf : animal naming and fas ] , stroop color - word and letter / number sequencing [ ln sequence ] ) ; learning and working memory ( rey auditory verbal learning tests , four - word short - term memory [ 4wstm ] , and rey - osterrieth complex figure [ rocf ] delayed task ) ; and visuoconstruction skills ( rocf copy task [ rocf - copy ] ) .
participant characteristics were compared using the t test , fisher exact test , and wilcoxon rank sum test , as applicable ( table 1 ) .
comparison of characteristics of participants without t1d (  no t1d  ) and with t1d (  t1d  ; edc ) and by degree of cognitive impairment * among participants with t1d all measures were collected at the time of neurocognitive assessment ( 20102013 ) unless otherwise noted .
data are n ( % ) , mean  sd , or median ( interquartile range ) .
* degree of cognitive impairment :  0  = no cognitive impairment , no test scores 1.5 sd worse than published norms ;  1  = mild , only one test score 1.5 sd worse than the published norm ;  2  = clinically relevant , two or more test scores 1.5 sd worse than published norms .
for participants with t1d , systolic blood pressure ( sbp ) 140 mmhg or diastolic blood pressure ( dbp ) 90 mmhg or self - report of ever using antihypertensive medication at any edc physical exam from baseline ( 19861988 ) through the time of neurocognitive assessment ( 20102013 ) ; for participants without t1d , a history of high blood pressure or use of antihypertensive medication based on self - report at the time of neurocognitive assessment .
raw cognitive test scores were compared between groups using ancova , adjusted for education ( table 2 ) .
standardized effect sizes for between - group differences in test scores were computed using cohen d t(n1 + n2)/df(n1  n2 ) and were classified as small ( d < 0.30 ) , moderate ( d 0.300.60 ) , or large ( d  0.60 ) ( 19 ) ( supplementary fig .
2 ) . raw cognitive test scores for participants with t1d ( edc ) and participants without t1d
* p value for mean difference in test score , adjusted for years of education .
effect size ( cohen d ) calculated as t(n1 + n2)/df(n1  n2 ) to account for unequal sample sizes and unequal variances ( source : http://www.uccs.edu/lbecker/effect-size.html , accessed 11 december 2014 ) .
tasks in which a higher score indicates worse performance ; in all other tasks , higher scores indicate better performance .
individual raw test scores 1.5 sd worse than published norms ( 1012 ) were considered  impaired .  between - group differences on impairment for each cognitive test were compared using the fisher exact test ( fig .
1 ) . a : percentage of participants scoring 1.5 sd worse than published normative data in no , one , two , three , or four or more tests .
white bars indicate participants without t1d ; black bars represent participants with t1d .  any 2 +  indicates the percentage of participants scoring 1.5 sd worse than published normative data on two or more tests , thereby meeting the study definition of clinically relevant cognitive impairment .
b : percentage of participants with t1d ( black bars ) and without t1d ( white bars ) scoring 1.5 sd worse than published normative data , by test . only tasks with statistically significant ( p < 0.05 ) between - group differences are shown .
the seven tasks with statistically significant between - group differences in impairment were used to determine levels of cognitive impairment : none = no test scores  impaired  ; mild = only one test score impaired ; clinically relevant = two or more test scores impaired . this classification scheme is validated and used in epidemiologic studies to assess cognitive impairment in community - dwelling adults aged 75 years ( 13 ) .
between - group differences in the level of cognitive impairment were assessed using the fisher exact test , controlling for education ( fig .
1 ) . to examine factors related to between - group differences in cognitive impairment , characteristics that differed between groups ( false discovery rate [ fdr ] = 0.20 ; table 1 ) were entered in ordinal logistic regression models with level of cognitive impairment as the outcome and t1d status as the main covariate ( table 3 ) .
ordinal logistic ( proportional odds ) regression models showing the independent effects of t1d on the odds of cognitive impairment level ors here should be interpreted proportionately as the odds of any cognitive impairment ( one or more vs. no tests impaired at 1.5 sd compared with published norms ) ; also two or more vs. no or one test impaired .
different variables were included in each model : model 1 , t1d ; model 2 , t1d + years of education ; model 3 , t1d + years of education + diastolic blood pressure ; model 4 , t1d + years of education + history of high blood pressure ; model 5 , t1d + years of education + estimated weekly physical activity . *
statistically significant using bonferroni correction ( model 1 : p < 0.05 ; model 2 : p < 0.03 ; models 35 , p < 0.02 ) . sensitivity analysis , excluding participants with a history of high blood pressure ( 140/90 mmhg or using antihypertensive medication ) , was conducted to ensure that the imbalance in high blood pressure was not confounding results . in analyses restricted to participants with t1d
, characteristics were compared first across level of cognitive impairment using the fisher exact test for categorical variables and anova for continuous variables ( table 1 ) .
characteristics that differed at fdr = 0.20 then were entered into separate ordinal logistic regression models with level of cognitive impairment as the outcome , controlling for years of education ( supplementary table 1 ) .
all models met the proportional odds assumption ( p > 0.1 ) . to adjust for multiple comparisons
education - adjusted p values were sorted from lowest to highest , then the benjamini - hochberg correction was applied to identify statistically significant variables , accepting that 20% may be false positives .
this corresponded to a p value of 0.03 ( supplementary table 2 ) when comparing factors between participants by t1d status ( table 1 ,  no t1d  and  t1d  columns ) , of 0.06 ( supplementary table 3 ) when comparing factors among participants with t1d by cognitive status ( table 1 ,  degree of cognitive impairment 
columns ) , and of 0.10 ( supplementary table 4 ) when comparing cognitive test scores by t1d status ( table 2 ) .
we chose this method over family - wise correction methods because of the paucity of prior studies ; we would rather falsely identify factors as deserving further investigation than reject factors that actually warrant additional study . in the ordinal logistic regression models ( table 3 , supplementary table 1 ) ,
middle - aged adults with t1d ( n = 97 ; mean age and duration of diabetes 49 and 41 years , respectively ) were recruited from the pittsburgh epidemiology of diabetes complications ( edc ) study , an ongoing prospective study of individuals diagnosed before age 18 years and listed in the children s hospital of pittsburgh s diabetes registry .
the first edc clinical assessment occurred in 19861988 ( n = 658 ; mean age and duration of diabetes 28 and 19 years , respectively ) .
biennial physical exams and questionnaires occurred through 19961998 , with an additional exam in 20042006 ( for details see ref .
all locally dwelling edc participants as of 1 january 2010 ( n = 263 ) were invited to participate in an ancillary neuroimaging / neurocognitive study . of those ,
81 refused , 26 never responded , and 2 were lost to follow - up . of the 154 interested , 37 were ineligible for mri ( e.g. , metallic implants , claustrophobic ) and 5 had scheduling conflicts , leaving 112 eligible and scheduled for neuroimaging / neurocognitive testing .
of these , three failed to show for their scheduled visit . on their scheduled testing date ,
another three refused the mri and nine refused the cognitive test battery , yielding an analytic sample of n = 97 ( supplementary fig .
adults without t1d who were participating in an observational study of the effects of prehypertension ( blood pressure higher than  normal  but not high enough to qualify as hypertensive ) on cerebral structure and function served as a comparison group .
inclusion criteria were age 3560 years , local to pittsburgh , and blood pressure within the values of 120139/8089 mmhg .
of the 414 who responded to the mailing / advertisement and were screened to participate , 110 were ineligible for mri , 60 changed their mind , and 14 withdrew , leaving 230 enrolled ( mean age 46 years ) . to mirror the edc s primarily caucasian racial distribution ,
only caucasian participants with complete neuroimaging / neurocognitive data as of august 2013 ( n = 138 ) were included .
all study procedures received local institutional review board approval , and all participants provided informed consent before any research procedures were initiated .
for all participants , blood pressure , bmi , and serum glucose were measured using standardized techniques at the time of cognitive testing .
participants with serum glucose 70 mg / dl were given a snack then retested after 15 min ; no cognitive testing was performed if serum glucose was 70 mg / dl .
weekly caloric expenditure ( kcal ) was estimated using the self - report paffenbarger questionnaire . as part of edc ,
metabolic control and blood pressure were assessed biennially from baseline through 19961998 , again in 20042006 , and at the time of neurocognitive testing ( 20102013 ) ; this allowed calculations of long - term average blood pressure and glycemic control ( hba1c and  a1c months ,  a calculated measure assessing the degree and duration of hyperglycemia [ for details see ref .
16 ] ) . in 19901992 , arterial health was assessed via the ankle - brachial index ( abi ) ; two readings were averaged , then dichotomized as < 1.3 or > 1.3/noncompressible .
an abi > 1.3 is correlated with medial arterial calcification ( 17 ) , which is associated with arterial stiffening ( 18 ) .
prevalence of t1d complications ( nephropathy , coronary artery disease , distal symmetric polyneuropathy , cardiac autonomic neuropathy , retinopathy ) was assessed biennially from baseline through 19961998 , then again in 20042006 , using highly standardized methods ( for details see ref .
cognitive measures included estimated verbal intelligence ( north american adult reading test [ naart ] ) ; psychomotor efficiency ( digit symbol substitution test [ dsst ] and grooved pegboard [ gp ] ) ; executive function ( trail making test , part b [ tmtb ] , verbal fluency [ vf : animal naming and fas ] , stroop color - word and letter / number sequencing [ ln sequence ] ) ; learning and working memory ( rey auditory verbal learning tests , four - word short - term memory [ 4wstm ] , and rey - osterrieth complex figure [ rocf ] delayed task ) ; and visuoconstruction skills ( rocf copy task [ rocf - copy ] ) .
cognitive measures included estimated verbal intelligence ( north american adult reading test [ naart ] ) ; psychomotor efficiency ( digit symbol substitution test [ dsst ] and grooved pegboard [ gp ] ) ; executive function ( trail making test , part b [ tmtb ] , verbal fluency [ vf : animal naming and fas ] , stroop color - word and letter / number sequencing [ ln sequence ] ) ; learning and working memory ( rey auditory verbal learning tests , four - word short - term memory [ 4wstm ] , and rey - osterrieth complex figure [ rocf ] delayed task ) ; and visuoconstruction skills ( rocf copy task [ rocf - copy ] ) .
participant characteristics were compared using the t test , fisher exact test , and wilcoxon rank sum test , as applicable ( table 1 ) .
comparison of characteristics of participants without t1d (  no t1d  ) and with t1d (  t1d  ; edc ) and by degree of cognitive impairment * among participants with t1d all measures were collected at the time of neurocognitive assessment ( 20102013 ) unless otherwise noted .
data are n ( % ) , mean  sd , or median ( interquartile range ) .
* degree of cognitive impairment :  0  = no cognitive impairment , no test scores 1.5 sd worse than published norms ;  1  = mild , only one test score 1.5 sd worse than the published norm ;  2  = clinically relevant , two or more test scores 1.5 sd worse than published norms . statistically significant using an fdr of 0.20 . for participants with t1d , systolic blood pressure ( sbp ) 140 mmhg or diastolic blood pressure ( dbp ) 90 mmhg or self - report of ever using antihypertensive medication at any edc physical exam from baseline ( 19861988 ) through the time of neurocognitive assessment ( 20102013 ) ; for participants without t1d , a history of high blood pressure or use of antihypertensive medication based on self - report at the time of neurocognitive assessment .
raw cognitive test scores were compared between groups using ancova , adjusted for education ( table 2 ) .
standardized effect sizes for between - group differences in test scores were computed using cohen d t(n1 + n2)/df(n1  n2 ) and were classified as small ( d < 0.30 ) , moderate ( d 0.300.60 ) , or large ( d  0.60 ) ( 19 ) ( supplementary fig .
2 ) . raw cognitive test scores for participants with t1d ( edc ) and participants without t1d * p value for mean difference in test score , adjusted for years of education .
effect size ( cohen d ) calculated as t(n1 + n2)/df(n1  n2 ) to account for unequal sample sizes and unequal variances ( source : http://www.uccs.edu/lbecker/effect-size.html , accessed 11 december 2014 ) .
. tasks in which a higher score indicates worse performance ; in all other tasks , higher scores indicate better performance .
individual raw test scores 1.5 sd worse than published norms ( 1012 ) were considered  impaired . 
between - group differences on impairment for each cognitive test were compared using the fisher exact test ( fig .
a : percentage of participants scoring 1.5 sd worse than published normative data in no , one , two , three , or four or more tests .
any 2 +  indicates the percentage of participants scoring 1.5 sd worse than published normative data on two or more tests , thereby meeting the study definition of clinically relevant cognitive impairment .
b : percentage of participants with t1d ( black bars ) and without t1d ( white bars ) scoring 1.5 sd worse than published normative data , by test . only tasks with statistically significant ( p < 0.05 ) between - group differences are shown .
the seven tasks with statistically significant between - group differences in impairment were used to determine levels of cognitive impairment : none = no test scores  impaired  ; mild = only one test score impaired ; clinically relevant = two or more test scores impaired . this classification scheme is validated and used in epidemiologic studies to assess cognitive impairment in community - dwelling adults aged 75 years ( 13 ) .
between - group differences in the level of cognitive impairment were assessed using the fisher exact test , controlling for education ( fig .
1 ) . to examine factors related to between - group differences in cognitive impairment , characteristics that differed between groups ( false discovery rate [ fdr ] = 0.20 ; table
1 ) were entered in ordinal logistic regression models with level of cognitive impairment as the outcome and t1d status as the main covariate ( table 3 ) .
ordinal logistic ( proportional odds ) regression models showing the independent effects of t1d on the odds of cognitive impairment level ors here should be interpreted proportionately as the odds of any cognitive impairment ( one or more vs. no tests impaired at 1.5 sd compared with published norms ) ; also two or more vs. no or one test impaired .
different variables were included in each model : model 1 , t1d ; model 2 , t1d + years of education ; model 3 , t1d + years of education + diastolic blood pressure ; model 4 , t1d + years of education + history of high blood pressure ; model 5 , t1d + years of education + estimated weekly physical activity . *
statistically significant using bonferroni correction ( model 1 : p < 0.05 ; model 2 : p < 0.03 ; models 35 , p < 0.02 ) . sensitivity analysis , excluding participants with a history of high blood pressure ( 140/90 mmhg or using antihypertensive medication ) , was conducted to ensure that the imbalance in high blood pressure was not confounding results . in analyses restricted to participants with t1d
, characteristics were compared first across level of cognitive impairment using the fisher exact test for categorical variables and anova for continuous variables ( table 1 ) .
characteristics that differed at fdr = 0.20 then were entered into separate ordinal logistic regression models with level of cognitive impairment as the outcome , controlling for years of education ( supplementary table 1 ) .
all models met the proportional odds assumption ( p > 0.1 ) . to adjust for multiple comparisons
education - adjusted p values were sorted from lowest to highest , then the benjamini - hochberg correction was applied to identify statistically significant variables , accepting that 20% may be false positives .
this corresponded to a p value of 0.03 ( supplementary table 2 ) when comparing factors between participants by t1d status ( table 1 ,  no t1d  and  t1d  columns ) , of 0.06 ( supplementary table 3 ) when comparing factors among participants with t1d by cognitive status ( table 1 ,  degree of cognitive impairment 
columns ) , and of 0.10 ( supplementary table 4 ) when comparing cognitive test scores by t1d status ( table 2 ) .
we chose this method over family - wise correction methods because of the paucity of prior studies ; we would rather falsely identify factors as deserving further investigation than reject factors that actually warrant additional study . in the ordinal logistic regression models ( table 3 , supplementary table 1 ) ,
both cohorts were comparable in age , male - to - female distribution , systolic blood pressure , bmi , and apolipoprotein e4 ( apoe4 ) status ( table 1 ) . compared with participants without t1d ,
participants with t1d were significantly more likely to have a history of high blood pressure ( 38% vs. 8% ; p < 0.0001 ) , higher serum glucose ( 174.5 vs. 91.3 mg / dl ; p < 0.0001 ) , lower diastolic blood pressure ( 66 vs. 80 mmhg ; p < 0.0001 ) , and lower estimated weekly physical activity ( 1092 vs. 1628 kcal ; p = 0.03 ) ( table 1 ) . compared with participants without t1d , those with t1d had lower raw cognitive test scores on measures of psychomotor speed , executive function , visuoconstruction ability , and verbal intelligence ( table 2 ) . large effect sizes ( d  0.60 ) were found for naart , dsst , gp , and rocf - copy .
moderate effect sizes ( d 0.30.6 ) were found for stroop color - word , tmtb , vf , ln sequence , and 4wstm 5-s list scores ( table 2 , supplementary fig .
range , but between - group differences on this and other memory test scores were not statistically significant using an fdr of 0.20 .
( i.e. , the raw test score was 1.5 sd worse than the published norm ) . compared with participants without t1d ,
those with t1d had significantly higher rates of impairment on tests of psychomotor speed ( dsst : 25% vs. 8% ; gp : 45% vs. 10% ) , executive function ( tmtb : 12% vs. 5% ; vf : 10% vs. 2% ; vf animals : 8% vs. 1% ; stroop color - word : 8% vs. < 1% ) , and visuoconstruction ability ( rocf - copy : 20% vs. 4% ) ( fig .
participants with t1d were also more likely to have two or more tests impaired , hence meeting our definition of clinically relevant cognitive impairment ( 28% vs. 5% ; p < 0.0001 ; fig .
1a ) . in ordinal logistic regression models with level of cognitive impairment as the outcome , having t1d was related to fivefold increased odds of having cognitive impairment ( table 3 ) .
importantly , no other factors significantly modified this between - group difference . in sensitivity analyses excluding participants with a history of high blood pressure ,
having t1d remained significantly associated with higher odds of cognitive impairment ( odds ratio [ or ] 4.35 ; p = 0.001 ) , and no other factors significantly modified this relationship .
when comparing participants with t1d by level of cognitive impairment , we found no statistically significant differences by sex , age , t1d duration , age at t1d diagnosis , serum glucose at time of cognitive testing , estimated glomerular filtration rate , apoe4 status , physical activity , blood pressure measures , or prevalence of coronary artery disease , cardiac autonomic neuropathy , or overt neuropathy measured 5 years earlier ( table 1 ) . compared with cognitively normal participants with t1d , those with mild or clinically relevant cognitive impairment had significantly fewer years of education , higher bmi , and worse long - term glycemic control ; were more likely to have a 20-year prior average abi > 1.3 ; and were more likely to have prevalent distal symmetric polyneuropathy or proliferative retinopathy measured 5 years earlier ( table 1 )
relationships remained similar when controlling for serum glucose or a1c at the time of neurocognitive testing . among participants with t1d , ordinal logistic regression models with level of cognitive impairment as the outcome showed that having a 14-year ( 19962013 ) average hba1c  7.5% ( 58 mmol / mol ) tripled the odds of cognitive impairment ( supplementary table 1 , model 1 ) .
results were similar for prevalent proliferative retinopathy or distal symmetric polyneuropathy ( supplementary table 1 , models 2 and 3 ) .
each unit increase in bmi was associated with a 10% increased odds of cognitive impairment ( supplementary table 1 , model 4 ) .
an average abi > 1.3/noncompressible quadrupled the odds of cognitive impairment ( supplementary table 1 , model 5 ) .
these relationships remained statistically significant after adjusting for years of education and the interval of time from the most recent edc exam ( 20042006 ) to the time of neurocognitive testing after bonferroni correction .
unlike previous reports of mild / modest cognitive dysfunction in young adults with t1d ( 1,2 ) , we detected clinically relevant cognitive impairment in 28% of our middle - aged participants with t1d .
this prevalence rate in our t1d cohort is comparable to the prevalence of mild cognitive impairment typically reported among community - dwelling adults aged 85 years and older ( 29% ) ( 20 ) .
we know of only one prior study that investigated clinically relevant cognitive impairment in t1d , and this was done in a pediatric population ( 4 ) .
overall , 12.8% of the pediatric participants with t1d met this early study s definition of clinically relevant cognitive impairment , a rate less than half that observed in our middle - aged population with t1d ( 28% ) .
interestingly , rates observed in the participants who did not have t1d were similar ( 56% ) in both studies .
this suggests that , for people without t1d , the rate of cognitive impairment remains basically unchanged from childhood into middle age , whereas the rate more than doubles over the same time among people with childhood - onset t1d . unlike the pediatric study
, we found no effect of early versus late age at t1d diagnosis ( age < 6 or > 6 years ) on cognitive impairment .
it is possible that during youth an earlier t1d onset contributes to worse brain function , but this effect becomes secondary to other factors as people with t1d age , prolonging their exposure to the deleterious effects of this metabolic disorder .
our findings contradict results from two previous studies of older participants with t1d , which reported  mild disturbances in cognitive function  ( 21 ) and no between - group differences in the rate of cognitive decline ( 22 ) .
it is important to note differences between our study and these prior studies that may contribute to the disparate findings .
only 33% of the participants in the earlier studies were diagnosed during childhood , whereas 100% of our participants with t1d were diagnosed during childhood .
consequently , although younger , with a mean age of 49 years compared with 61 ( 21 ) and 65 years ( 22 ) , our participants with t1d had a longer t1d duration ( mean 41 , 34 , and 38 years , respectively ) .
we postulate that the developing brain ( i.e. , during childhood ) may be especially vulnerable to insults of glycemic dysregulation and fluctuating insulin concentrations compared with the adult brain .
while mild cognitive differences can be detected early , more severe effects may become especially apparent later in life as these individuals grow older and experience the effects of normal age - related changes in brain function and structure in combination with the effects of long - term t1d and its comorbidities ( e.g. , hypertension , microvascular complications ) .
while the dcct / edic study found  no evidence of substantial long - term declines in cognitive function  over 18 years ( 23 ) , many of the dcct participants were diagnosed during adulthood ( at dcct baseline , mean age 27.0 years and mean duration of diabetes 5.7 years ) , unlike our cohort that includes only individuals diagnosed during childhood .
in addition , the dcct participants were young adults at their baseline neurocognitive exam and displayed relatively good metabolic control .
having t1d was the only factor significantly associated with the between - group difference in clinically relevant cognitive impairment in our sample .
traditional risk factors for age - related cognitive impairment , in particular older age and high blood pressure ( 24 ) , were not related to the between - group difference we observed .
the design of our study does not allow us to determine whether these traditional risk factors contributed to the development and/or progression of cognitive impairment in these participants , only that these factors were not related to the degree of cognitive impairment already present in these participants at the time of cognitive testing . among participants with t1d
, a 14-year average hba1c 7.5% ( 58 mmol / mol ) , prevalent distal symmetric polyneuropathy , and proliferative retinopathy assessed 5 years earlier were related to cognitive impairment , with effect sizes larger than those reported in prior studies ( 21,25 ) .
two other measures of glycemic control , hba1c > 7.5% ( 58 mmol / mol ) at the time of cognitive testing and 
25-year a1c months ,  also were related to higher odds of having cognitive impairment .
we chose to study the relationship between cognitive impairment and 14-year average a1c rather than 
because the latter is not widely understood ; we chose 14-year average a1c rather than a1c at a single assessment concurrent with cognitive testing to assess the chronicity of hyperglycemia .
all analyses were repeated , controlling separately for serum glucose then for a1c at the time of cognitive testing , to ensure glucose concentrations were not confounding study results .
similar to previous studies of younger adults with t1d ( 14,26 ) , we found no relationship between the number of severe hypoglycemic episodes and cognitive impairment .
rather , we found that chronic hyperglycemia , via its associated vascular and metabolic changes , may have triggered structural changes in the brain that disrupt normal cognitive function . like others ( 14 ) , we found no statistically significant relationships between cognitive impairment and apoe4 status . whereas earlier studies found relationships between cognitive dysfunction and age at t1d diagnosis ( 4,2729 ) , diabetes duration ( 29,30 ) , and high blood pressure ( 21,29,30 ) ,
this could be a result of our outcome of cognitive impairment compared with previous studies outcome of cognitive dysfunction .
in addition , participants in those earlier studies were younger , on average , than our participants and may therefore have not yet developed cognitive impairment .
we also identified two less - studied factors related to cognitive impairment in our sample .
first , we found that higher bmi was related with higher odds of cognitive impairment ( or 1.10 ; table 3 ) , similar to results reported by brismar et al .
( 29 ) showing relationships between higher bmi and deficits in psychomotor speed as well as general intelligence in adults with t1d .
while the exact mechanism relating bmi and cognitive function remains unclear , one plausible route is via an inflammatory pathway ( 31 ) . in animal models of t1d , higher levels of circulating glucocorticoids and higher susceptibility to stress were associated with high bmi , increased brain inflammation , and reduced neurogenesis ( 32 ) .
higher bmi could also indicate insulin resistance , which also is related to worse cognitive outcomes in older participants who are healthy or have type 2 diabetes ( 33 ) .
future studies should further investigate the influence of bmi on cognitive function in young participants with t1d to determine whether this could be a risk factor suitable for early intervention .
second , we found that participants with an average abi > 1.3/noncompressible had quadrupled odds of clinically relevant cognitive impairment .
high abi is a marker of subclinical vascular conditions including atherosclerosis , vessel stiffness , and calcification , all of which are known risk factors for cognitive impairment in older adults without t1d ( 34,35 ) .
peripheral vascular stiffness , as a result of endothelial dysfunction , may serve as an indicator of early changes to brain vasculature and structure ( 36 ) . as an example
, hepatic hypoperfusion resulting from endothelial dysfunction leads to  increased adhesion of circulating inflammatory cells to the endothelium , activation of the coagulation cascade and constriction of the microvasculature  ( 37 ) .
cerebral hypoperfusion likely exerts similar effects on the brain s vasculature ; diffuse subclinical ischemia and resultant damage to oligodendrocytes and focal necrosis in gray and white matter offer a mechanistic explanation for the relationship with cognitive impairment .
while the applicability of this finding is limited because of the small sample size , this novel potential risk factor deserves further investigation in participants with t1d .
performance on several neurocognitive tests used in this study ( e.g. , dsst , gp , rocf - copy ) depend on visual acuity and motor capabilities , skills that are compromised in participants with t1d with proliferative retinopathy and distal symmetric polyneuropathy . while these complications may contribute to poor performance on these tasks , psychomotor speed and executive function appear to be affected even in pediatric populations with t1d , well before such microvascular complications occur ( 3,4 ) .
furthermore , performance on several tasks requiring the same degree of visual acuity and fine motor skills ( e.g. , the rocf delayed task ) did not differ by cognitive status among participants with t1d , suggesting that prevalent retinopathy and/or polyneuropathy alone do not explain the cognitive impairment observed in these individuals .
rather , it suggests that long - term t1d causes microvascular damage in the brain similar to that known to affect the eyes and nerves , thereby explaining why participants with proliferative retinopathy and distal symmetric polyneuropathy were more likely to meet the study definition of clinically relevant cognitive impairment .
the number of participants with t1d completing each neurocognitive task varied ( see supplementary fig .
however , the completers did not significantly differ from the noncompleters by retinopathy , polyneuropathy , 14-year average a1c > 7.5% ,
overall , incompleteness was due to time constraints , that is , insufficient time to complete all tests within the 90 min allotted : 12 participants arrived at the cognitive testing center 10 min late , and another 6 were hypoglycemic , requiring at least 1530 min for serum glucose concentrations to normalize before initiating cognitive testing .
lack of time affected completion of the final tasks ( fas , vf animals , stroop , gp ) ; we do not believe this was dependent on cognitive status .
first , we included only participants with childhood - onset diabetes ; the cognitive effects of t1d on participants diagnosed during adulthood may differ from our participants who were exposed to chronic hyperglycemia in childhood , during crucial stages of brain and cognitive functioning development ( 38 ) . in addition
, 99% of our participants are caucasian , whereas 93% of people diagnosed with t1d in allegheny county , pennsylvania , from 19651979 were caucasian ( 39 ) . a survivor bias may be present in that these participants have survived with t1d for a substantial period of time .
a selection bias is also possible ; those participating in this cognitive study are , in general , healthier than the parent edc cohort , especially since the eligibility criteria for participation in the cognitive study included being able to undergo brain imaging .
many causes of mortality and morbidity that prevented participation in this study are related to cognitive impairment , potentially underestimating its true prevalence in t1d . because of the study design , we can not determine direction of the relationships between cognitive impairment and factors assessed concurrently , such as a1c on the day of cognitive testing ; it could be that those with worse cognitive impairment are less able to manage their diabetes , leading to higher a1c concentrations .
the study design also prohibits determination of the life stage at which clinically relevant cognitive impairment first developed in our participants .
strengths of this study include the use of a well - defined cohort with over 20 years of data , thus allowing computation of long - term trajectories of risk factor profiles , and the use of an extensive neuropsychological test battery to assess multiple cognitive domains .
the cognitive impairment algorithm has been used in previous studies ( 13 ) , is easily replicable , and could be adapted by others to improve comparability across studies . in summation , results of this study show that a large percentage of middle - aged adults with childhood - onset t1d are currently living with clinically relevant cognitive impairment .
the effects of cognitive impairment on these individuals  diabetes self - management , health service utilization , disability , and quality - of - life issues  deserve further investigation .
future studies with larger sample sizes and a wider range of ages at diagnosis are needed to improve our understanding of the development and progression of t1d - related cognitive impairment .
such studies should use repeated neurocognitive testing , beginning shortly after the time of diagnosis .
furthermore , incorporating repeated neuroimaging with extensive measures of metabolic control and vascular health would help to clarify the mechanisms contributing to the development of cognitive impairment in these individuals .
 objectivethe aim of this study was to investigate the presence and correlates of clinically relevant cognitive impairment in middle - aged adults with childhood - onset type 1 diabetes ( t1d).research design and methodsduring 20102013 , 97 adults diagnosed with t1d and aged < 18 years ( age and duration 49  7 and 41  6 years , respectively ; 51% female ) and 138 similarly aged adults without t1d ( age 49  7 years ; 55% female ) completed extensive neuropsychological testing . 
 biomedical data on participants with t1d were collected periodically since 19861988 . 
 cognitive impairment status was based on the number of test scores 1.5 sd worse than demographically appropriate published norms : none , mild ( only one test ) , or clinically relevant ( two or more tests).resultsthe prevalence of clinically relevant cognitive impairment was five times higher among participants with than without t1d ( 28% vs. 5% ; p < 0.0001 ) , independent of education , age , or blood pressure . 
 effect sizes were large ( cohen d 0.60.9 ; p < 0.0001 ) for psychomotor speed and visuoconstruction tasks and were modest ( d 0.30.6 ; p < 0.05 ) for measures of executive function . among participants with t1d , prevalent cognitive impairment was related to 14-year average a1c > 7.5% ( 58 mmol / mol ) ( odds ratio [ or ] 3.0 ; p = 0.009 ) , proliferative retinopathy ( or 2.8 ; p = 0.01 ) , and distal symmetric polyneuropathy ( or 2.6 ; p = 0.03 ) measured 5 years earlier ; higher bmi ( or 1.1 ; p = 0.03 ) ; and ankle - brachial index 1.3 ( or 4.2 ; p = 0.01 ) measured 20 years earlier , independent of education.conclusionsclinically relevant cognitive impairment is highly prevalent among these middle - aged adults with childhood - onset t1d . in this aging cohort , chronic hyperglycemia and prevalent microvascular disease 
 were associated with cognitive impairment , relationships shown previously in younger populations with t1d . 
 two additional potentially modifiable risk factors for t1d - related cognitive impairment , vascular health and bmi , deserve further study . 
Introduction
Research Design and Methods
Participants
Measures
Cognitive Assessment
Statistical Analyses
Results
Conclusions
Supplementary Material