cognitive dysfunction and diabetes mellitus

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Cognitive Dysfunction and Diabetes Mellitus

Christopher T. Kodl and Elizabeth R. Seaquist

Department of Medicine, Division of Endocrinology and Metabolism, University of Minnesota, Minneapolis, Minnesota55455

The deleterious effects of diabetes mellitus on the retinal,renal, cardiovascular, and peripheral nervous systems arewidely acknowledged. Less attention has been given to theeffect of diabetes on cognitive function. Both type 1 and type 2diabetes mellitus have been associated with reduced per-formance on numerous domains of cognitive function. Theexact pathophysiology of cognitive dysfunction in diabetes isnot completely understood, but it is likely that hyperglycemia,vascular disease, hypoglycemia, and insulin resistance play

significant roles. Modalities to study the effect of diabetes onthe brain have evolved over the years, including neurocogni-tive testing, evoked response potentials, and magnetic reso-nance imaging. Although much insightful research has exam-ined cognitive dysfunction in patients with diabetes, moreneeds to be understood about the mechanisms and naturalhistory of this complication in order to develop strategies forprevention and treatment. (Endocrine Reviews 29: 494511,2008)

I. IntroductionII. Cognitive Dysfunction in Patients with Diabetes

A. Type 1 diabetesB. Type 2 diabetesC. Hypoglycemia and cognitive dysfunctionD. Section summary

III. Pathophysiology of Cognitive Dysfunction in DiabetesA. The role of hyperglycemiaB. The role of vascular diseaseC. The role of hypoglycemiaD. The role of insulin resistance and amyloid

IV. Modalities for Assessment of Cognitive Dysfunction inPatients with Diabetes

V. Future DirectionsVI. Conclusion

I. Introduction

DIABETES MELLITUS IS a complex metabolic diseasethat can have devastating effects on multiple organsin the body. Diabetes is the leading cause of end stage renaldisease in the United States (1) and is also a common causeof vision loss, neuropathy, and cardiovascular disease. A lessaddressed and not as well recognized complication of dia-

betes is cognitive dysfunction. Patients with type 1 and type2 diabetes mellitus have been found to have cognitive deficits

that can be attributed to their disease. Both hypoglycemiaand hyperglycemia have been implicated as causes of cog-

nitive dysfunction, and many patients fear that recurrenthypoglycemia will impair their memory over time. Althoughmuch research has been done, the pathophysiology under-lying this complication is not well understood, and the mostappropriate methods to diagnose, treat, and prevent cogni-tive dysfunction in diabetes have not yet been defined. In thisarticle, we will review the nature of cognitive dysfunction intype 1 and type 2 diabetes mellitus, the pathophysiology ofcognitive dysfunction secondary to diabetes, methodologiesused to assess cognitive deficits in patients with diabetes, andpotential future directions of research that are needed toadvance our understanding of this often overlooked com-

plication of diabetes.The purpose of this article is to present a comprehensivereview of the literature regarding the subject of cognitivedysfunction in diabetes mellitus. To do this, we performedMEDLINE searches for such key words and terms as diabetesmellitus, cognitive function, cognition, hypoglycemia,insulin resistance, and Alzheimers disease, among others.We then pursued articles referenced in these sources. Althoughthis is a comprehensive review, it is not exhaustive. In addition,it should be noted that the field of cognitive dysfunction indiabetes is still in its early stages. It must be remembered thatalthough there have been many significant contributions re-garding the association of diabetes and cognitive dysfunctionand many hypotheses based on this association, the causativemechanisms of diabetes on cognitive dysfunction are still un-dergoing development.

II. Cognitive Dysfunction in Patients with Diabetes

A. Type 1 diabetes

Cognitive dysfunction in patients with diabetes mellituswas first noted in 1922, when patients with diabetes, whowere free from acidosis but usually not sugar free, werenoted to have impaired memory and attention on cognitivetesting compared with controls (2). Since then, there have

been many studies designed to better delineate the scope and

First Published Online April 24, 2008Abbreviations: AGE, Advanced glycation end product; APOE-4,

apolipoprotein E type 4; APP, amyloid precursor protein; DCCT, Dia-betes Control and Complications Trial; EEG, electroencephalograph(y);fMRI, functional MRI; GLUT, glucose transporter; HbA1c, glycated he-moglobin; MRI, magnetic resonance imaging; NMDA, N-methyl-d-aspartate; PET, positron emission tomography; PPAR-, peroxisomeproliferator-activated receptor-; SPECT, single photon emission com-puted tomography.

Endocrine Reviews is published by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving theendocrine community.

0163-769X/08/$20.00/0 Endocrine Reviews 29(4):494511Printed in U.S.A. Copyright 2008 by The Endocrine Society

doi: 10.1210/er.2007-0034

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magnitude of cognitive dysfunction in diabetes (Table 1). Themost common cognitive deficits identified in patients with

type 1 diabetes are slowing of information processing speed(36) and worsening psychomotor efficiency (3, 4, 7). How-ever, other deficits have been noted, including deficits inmotor speed (5, 810), vocabulary (7, 1113), general intel-ligence (12, 14), visuoconstruction (6, 12), attention (6), so-matosensory examination, motor strength (10), memory (7),and executive function (7, 14). Glycemic control appears toplay a role in cognitive performance in patients with type 1diabetes. Functions such as psychomotor efficiency, motorspeed (5, 15), attention, verbal IQ scores (1618), memory,and academic achievement (17) are improved with betterglycemic control. Specifically, an 18-yr follow-up of the Di-abetes Control and Complications Trial (DCCT) showed that

those patients with type 1 diabetes mellitus with a timeweighted mean glycated hemoglobin (HbA1c) less than 7.4%performed significantly better on tests of motor speed andpsychomotor efficiency than those subjects whose timeweighted mean HbAlc was greater than 8.8% (15). In addi-tion, slowing of all cognitive function, an increased numberof mental subtraction errors (19), loss of inhibition and focus(20), impaired speed of information processing, decreasedattention, and impaired working memory (21) have all beennoted during acute hyperglycemia in patients with type 1and type 2 diabetes.

A recent meta-analysis included 33 studies examining cog-nitive function in adult subjects with type 1 diabetes mellitus

(22). It found that there were significant reductions in overallcognition, fluid and crystallized intelligence, speed of infor-mation processing, psychomotor efficiency, visual and sus-tained attention, mental flexibility, and visual perception insubjects with type 1 diabetes compared with controls. Therewas no difference in memory, motor speed, selective atten-tion, and language. All studies included healthy matchedcontrol groups and used reliable testing measures at normal

blood glucose values. Most studies included in the meta-analysis controlled for depression; however, similar findingswere seen in those studies that did not control for depression.It is unclear whether any of these studies controlled for otherchronic diseases that could affect cognitive function. Worsecognition was associated with increased diabetes complica-

tions, but not with glycemic control in these populations.However, this last finding was confounded by the hetero-geneity of how different studies defined well vs. poorlycontrolled diabetes (22).

As was demonstrated in the work of Brands et al. (22),cognitive function may be worse in patients with type 1diabetes who experience other diabetes complications. Def-icits in fluid intelligence, information processing, attention,and concentration have been associated with the presence of

background retinopathy (23). Proliferative retinopathy, ma-crovascular complications, hypertension, and duration ofdiabetes were associated with poorer performance on testsmeasuring psychomotor speed and visuoconstruction abilityin patients with type 1 diabetes (46). Patients with distalsymmetrical polyneuropathy displayed worse cognitivefunction on most cognitive domains except for memory (5).However, other studies were unable to identify a relation-ship between impaired cognitive function and diabetic com-plications (24). Future study will be necessary to determinewhether there is a link between complications and alterations

in cognition.Although complications like retinopathy and nephropa-

thy usually require years of diabetes before becoming clin-ically apparent, the onset of cognitive impairment has beenfound to occur early in patients with type 1 diabetes. Deficitsin cognitive function have been detected as early as 2 yr afterdiagnosis in children with type 1 diabetes, and these patientsexperienced less positive changes than controls over time ingeneral intelligence, vocabulary, block design, speed of pro-cessing, and learning (12). Six years after diagnosis, thesesame subjects had impaired IQ, attention, processing speed,long-term memory, and executive function compared withcontrols (14). The age of onset of type 1 diabetes may also

contribute to the presence of cognitive dysfunction, becausethose who developed type 1 diabetes at less than 4 yr of agehad impaired executive skills, attention, and processingspeed when compared with those that were diagnosed after4 yr of age (14). Of note, chronic disease and time away fromschool (secondary to illness, etc.) were not controlled for inthese studies.

Interestingly, several studies have shown patient genderto influence neurocognitive function in patients with type 1diabetes mellitus. Skenazy and Bigler (10) found that menwith type 1 diabetes had reduced performance on oscillation,strength grip, and somatosensory testing compared withmale controls, and the magnitude of this difference was

greater than that measured between women with type 1diabetes and their gender-matched controls. In addition, adecline in verbal intelligence was seen in boys with type 1diabetes between the ages of 7 and 16, which correlated withworse glycemic control. This was not seen in girls of similarages (13). However, most human studies have not distin-guished between genders when describing results of neu-rocognitive testing, and therefore more controlled analysisshould be done before any conclusions are drawn.

Of note, the strength of these neurocognitive studies isvariable. Covariates that could affect neurocognitive testinginclude age, education, sex, history of other chronic illnesses,psychiatric disorders, neurological disorders, substanceabuse, absence from school, socioeconomic status, and hy-

TABLE 1. Summary of cognitive domains that have been found tobe negatively affected by type 1 diabetes mellitus

Slowing of information processing*Psychomotor efficiency*

Attention*MemoryLearning

Problem solvingMotor speed

VocabularyGeneral intelligence

Visuoconstruction*Visual perceptionSomatosensory examinationMotor strengthMental flexibility*Executive function

Domains marked by asterisks have particularly strong support-ing data.

Kodl and Seaquist Cognition and Diabetes Mellitus Endocrine Reviews, June 2008, 29(4):494 511 495



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poglycemia/hyperglycemia during testing. The reviewedre-ports controlled forat least some of these covariates,howevermost fail to control for all of them. For example, only twostudies that have been mentioned (6, 24) have reported con-trolling for hyperglycemia at the time of testing, which has

been proven to affect cognitive function (see Section II.A). Thecognitive domains that are affected by type 1 diabetes withthe best evidence based on our review are indicated in Table 1with an asterisk.

B. Type 2 diabetes

Patients with type 2 diabetes mellitus have also beenfound to have cognitive impairment (Table 2). Type 2 dia-

betes has been associated with decreases in psychomotorspeed (25, 26), frontal lobe/executive function (26 28), verbalmemory (29), processing speed (29), complex motor func-tioning (26), working memory (27, 28), immediate recall,delayed recall (30), verbal fluency (26, 31), visual retention(32), and attention (33). The impact of these subtle neuro-

cognitive deficits on the daily lives of patients with type 2diabetes is not clear. Sinclair et al. (34) found that subjectswith mini-mental status exam scores less than 23 fared worseon measures of self care and ability to perform activities ofdaily living. These subjects also displayed an increased needfor personal care and increased rates of hospitalization whencompared with controls. Patients with diabetes also have

been found to have slower walking speed, lack of balance,and increased falls associated with type 2 diabetes, butwhether the cerebral affects of diabetes contributed to theseabnormalities is debatable (35). Complicating the impact ofmild neurocognitive dysfunction secondary to diabetes ondaily living is the observation that patients with diabetes are

twice as likely to have depression (27, 36), which will alsonegatively affect cognitive function and daily activities. Type2 patients also have an increased incidence of Alzheimersdisease (3744) and increased incidence of vascular dementia(38, 42, 45). Recently, Bruce et al. (36) found that 17.5% ofelderly patients with type 2 diabetes had moderate to severedeficits in activities of daily living, 11.3% had cognitive im-pairment, and 14.2% had depression.

Glycemic control appears to play a role in determining thedegree of cognitive dysfunction detected in patients withtype 2 diabetes, although this has not uniformly been ob-

served (46). In a population of nearly 2000 postmenopausalwomen, Yaffe et al. (47) found that those with a HbA1c ofmore than 7.0% had a 4-fold increase in developing mildcognitive impairment. Grodstein et al. (30) found that elderlysubjects who took oral diabetic medication, unlike those oninsulin, had similar scores on general tests for cognition assubjects without diabetes. Other studies have demonstratedan inverse relationship between HbAlc and working mem-ory (27, 28), executive functioning (27), learning (26), andcomplex psychomotor performance (26, 48) in patients withtype 2 diabetes mellitus, supporting the hypothesis thatworsening glucose control leads to worsening cognitivefunction much like with type 1 diabetes. Also similar to type1 diabetes is the association between alterations in cognitivefunction in patients with type 2 diabetes and diabetes com-plications like peripheral neuropathy (28) and duration oftype 2 diabetes (25, 33).

Impaired glucose tolerance without diabetes is also a riskfactor for cognitive dysfunction. Multiple investigations ofpatients with impaired glucose tolerance have shown them

to have lower mini-mental status exam and long-termmemory scores (49), impaired verbal fluency (31), increasedAlzheimers dementia (39), and increased vascular dementia(38) compared with control subjects. These observations mir-ror the positive relationship found between hyperglycemiain patients without diabetes and cardiovascular disease(5052). The pathophysiology of this relationship is unclear,and there is evidence that both hyperglycemia and otheraspects of insulin resistance could contribute to this, whichwill be addressed later. Of note, however, not all studies foundthatpatients with impaired glucosetolerance (33, 53, 54)or type2 diabetes mellitus (54, 55) perform worse than normoglycemicindividuals.

However, like neurocognitive studies examining type 1diabetes, the strength of these neurocognitive studies eval-uating type 2 diabetes and impaired glucose tolerance isvariable. Although most of these studies controlled forage, there was uneven control for other covariates includ-ing education, psychiatric disorders, neurological disorders,hyperglycemia and hypoglycemia during testing, and chronicillness. The cognitive domains that are affected by type 2 dia-

betes with the best evidence based on our review are indicatedin Table 1 with an asterisk.

C. Hypoglycemia and cognitive dysfunction

Repetitive episodes of moderate to severe hypoglycemiahave been implicated as one possible etiology of cognitivedysfunction in diabetes. This is significant because the risk ofhypoglycemia increases as efforts to achieve the level ofglycemia necessary to minimize the risk of developingthe microvascular complications of diabetes are intensified(5658). The reason for severe hypoglycemia secondary tointensive insulin management is complex and multifactorial,however the initial intelligence of patients with type 1 dia-

betes before intensive management does not predispose tomore future hypoglycemia episodes, as shown by an analysisof data collected during the DCCT (59). During acute hypo-glycemia episodes, it has been shown that performanceon immediate verbal memory, immediate visual memory,

TABLE 2. Summary of cognitive domains that have been found tobe negatively affected by type 2 diabetes mellitus

Memory*Verbal memoryVisual retentionWorking memoryImmediate recallDelayed recall

Psychomotor speed*Executive function*Processing speedComplex motor function

Verbal fluencyAttentionDepression

Domains marked by asterisks have particularly strong support-ing data.

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working memory, delayed memory,visual-motorskills,visual-spatial skills, and global cognitive dysfunction are all impaired(60, 61). In a more recent study, prospective memory (that is,remembering to remember) and immediate and delayed re-call were both impaired secondary to hypoglycemia in patientswith type 1 diabetes, suggesting that impairments with bothrecall and learning/consolidation occur during hypoglycemia(62). Interestingly, in some studies there was no difference inreaction time (63), memory (62), and overall cognitive perfor-mance (61) between hypoglycemiaaware andunaware patientsduring hypoglycemic episodes, despite the factthat the glucoselevel at which the counterregulatory hormone response waselicited washigherin subjects with awarenessofhypoglycemia.

Although cognitive impairment may occur during hypo-glycemia, the effect of repetitive hypoglycemia on subse-quent cognitive function during euglycemia is less clear.Studies have shown impaired verbal IQ scores (14, 64), fullscale IQ scores (14, 20, 64), attention (20), verbal skills (11),short-term memory, verbal memory (17), vigilance (65), andvisual-spatial memory (8, 18) in patients with a history of

type 1 diabetes and severe hypoglycemia (defined as beingassociated with seizures, coma, or the need for external as-sistance), compared with patients with type 1 diabetes with-out a history of severe hypoglycemia. However, it is possiblethat some of these abnormalities could be the result ofslower, more deliberate completion of the tasks without lossof accuracy (66). More recently, no association between mul-tiple severe episodes of hypoglycemia and impaired cogni-tive function in patients with type 1 diabetes mellitus wasfound in an 18-yr follow-up of the DCCT (15). Although theDCCT follow-up has been regarded as a landmark study thatprovides reassurance to diabetologists and patients, it is im-portant to recognize its limitations, including the fact that it

did not randomize patients into a severe hypoglycemiagroup and a control group (because such randomizationwould be not only logistically impossible but also unethical).A lack of association between severe hypoglycemia and cog-nitive dysfunction was confirmed by other studies (23, 6871), as well as with a meta-analysis, which showed no as-sociation between hypoglycemia and cognitive function (22).Of note, however, most data analyzing the effects of hypo-glycemia look at young to middle-aged patients; data re-garding the impact of hypoglycemia on older individuals islacking.

One possible reason that some studies found an associa-tion between frequent hypoglycemia and cognitive dysfunc-

tion and others did not is that the positive investigations mayhave included subjects with diabetes onset earlier in life.Patients with type 1 diabetes diagnosed at less than 5 yr ofage may have more severe (often with seizures) and frequenthypoglycemia episodes than those diagnosed at ages olderthan 5 yr; these younger patients have been found to haveworse cognitive dysfunction (9, 18, 72, 73). The severity of thehypoglycemia as well as the susceptibility of young brains toinjury may explain the discrepancy (9, 74). Another expla-nation for discrepancy between reports is that subjects withmore hypoglycemia may have overall tighter glycemic con-trol, which may offset the neurocognitive damage from hy-poglycemia. This was most likely the case in the populationstudied by Kaufman et al. (17) in which children with more

frequent episodes of hypoglycemia (70 mg/dl) actuallyhad increased memory and verbal scores, as well as overall

better academic achievement when compared with less well-controlled children with diabetes.

D. Section summary

Clearly, much research has been done on cognitive dys-function in patients with type 1 and type 2 diabetes mellitus.Although results are not consistent and many different def-icits have been identified, some conclusions can be drawn. Inpatients with type 1 diabetes mellitus, deficits in speed ofinformation processing, psychomotor efficiency, attention,mental flexibility, and visual perception seem to be present,whereas in patients with type 2 diabetes, an increase inmemory deficits, a reduction in psychomotor speed, andreduced frontal lobe/executive function have been identi-fied. Severe hypoglycemic episodes may contribute to cog-nitive dysfunction in the young; however, as patients ageepisodes seem to have less of an influence. Finally, improved

diabetes control and decreased diabetic complications seemto be associated with less cognitive dysfunction, althoughthis association is clearer in patients with type 2 diabetes thanwith type 1 diabetes.

However, some questions remained unanswered. First, itis not clear whether cognitive impairments seen in neuro-cognitive testing result in meaningful deficits either sociallyor professionally. Given the subjective nature of assessingprofessional and social activities, it willbe difficult to addressthis question. Second, although the data suggest that hyper-glycemia contributes to cognitive impairment, the magni-tude of this contribution and how hyperglycemic one must

be to experience the ill effects of hyperglycemia on cognition

are not clear. Lastly, it is unknown whether mild neurocog-nitive impairments will progress to overt dementia. Largerandomized controlled trials such as the Epidemiology ofDiabetes Interventions and Complications (EDIC) study/DCCT and the ongoing Action to Control CardiovascularRisk in Diabetes (ACCORD) study should hopefully con-tinue to address these last two questions.

III. Pathophysiology of Cognitive Dysfunction in

Diabetes

The pathophysiology underlying the development of cog-nitive dysfunction in patients with diabetes has not been

completely elucidated. Many hypotheses with supportingevidence exist, including potential causative roles for hyper-glycemia, vascular disease, hypoglycemia, insulin resistance,and amyloid deposition (Fig. 1). Although further researchinto each of these candidate mechanisms is necessary, it may

be that the cause of cognitive dysfunction in patients withdiabetes will turn out to be a combination of these factors,depending on the patients type of diabetes, comorbidities,age, and type of therapy.

A. The role of hyperglycemia

As reviewed in Sections II.A and II.B, hyperglycemia ap-pears to be related to abnormalities in cognitive function in




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patients with both type 1 and type 2 diabetes. However, themechanisms through which hyperglycemia might mediate

this effect are less than clear. In other organs, hyperglycemiaalters function through a variety of mechanisms includingpolyol pathway activation, increased formation of advancedglycation end products (AGEs), diacylglycerol activation ofprotein kinase C, and increased glucose shunting in the hex-osamine pathway (7578). These same mechanisms may be

operative in the brain and induce the changes in cognitivefunction that have been detected in patients with diabetes.It has long been known that hyperglycemia increases

flux through the polyol pathway in nervous tissue. In thestreptozotocin-treated rat (glucose concentration 27.4 0.3mmol/liter vs. 5.9 0.1 mmol/liter in control rats), an in-crease in sorbitol was measured in cranial nerves, sciaticnerve, cerebral cortex, and retina. This accumulation wasreduced significantly when theanimals were treated with thealdose reductase inhibitor tolerstat (79). Another study look-ing at streptozotocin-treated rats (HbA1c 7.9 0.3 vs. 3.3 0.0 in control rats) also found that administering an aldosereductase inhibitor, sorbinil, reduced the accumulation of

brain tissue sorbitol and corrected the reduced cognitive

function normally seen in rats with hyperglycemia (80).

Whether this pathway contributes to neurocognitive dys-function in humans with diabetes is unknown.

The role of AGEs and receptors for AGE (RAGEs) in thedevelopment of cerebral complications of diabetes also re-mains uncertain. Diabetic mice (32% HbA1c vs. 12% in con-trol mice) with demonstrated cognitive impairment have

been found to have increased expression of RAGEs in neu-

rons and glial cells and damage to white matter and myelin(78), suggesting a possible role of RAGEs in the developmentof cerebral dysfunction (81). In humans, patients with dia-

betes and Alzheimers disease have been found to havegreater N-carboxymethyllysine (a type of AGE) staining on

brain slices obtained postmortem than patients with Alzhei-mers disease alone (82). However, a second autopsy studyfailedto find a difference in thequantity of AGE-likeglycatedprotein rich neurofibrillary tangles and senile plaques, likethose seen in patients with Alzheimers disease, betweenhuman subjects with diabetes and controls (83). Experimentsperformed in animal models provide limited evidence tosupport the hypothesis that AGE-induced brain injury may

be a mechanism through which hyperglycemia and diabetes

Cognitive Dysfunction in

Diabetes Mellitus

Hypoglycemia

Macrovascular

Disease

Cerebrovascular

Accident

Hyperglycemia-

Induced End Organ

Damage

Microvascular Disease

Insulin Resistance

Absence of

C-Peptide

Absence of

Apo4 Allele

FIG. 1. Summary of possible mechanistic contributors to cognitive dysfunction seen in diabetes mellitus. Not all mechanisms are present inevery patient.




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alter cerebral function. In vitro theadditionof AGEs to bovinebrain microvascular endothelial cells up-regulates both tis-sue factor mRNA (which induces blood coagulation) andreactive oxygen species through a mechanism that is re-versed with treatment by the free radical scavenger edara-vone (84). In addition, in a rat model of focal cerebral isch-emia, the infusion of AGEs increased cerebral infarct size,whereas the coadministration of aminoguanidine, an inhib-itor of AGE cross-linking, attenuated the infarct volume (85).

Few investigators have examined the role of diacylglycerolactivation of protein kinase C and increased glucose shuntingin the development of cognitive dysfunction in diabetes.Brain expression of protein kinase C- was shown to besignificantly increased in one untreated diabetic rat model(approximate blood glucose, 15 mmol/liter) compared withthe treated diabetic rat and control rats (approximate bloodglucose, 6 mmol/liter) (86), but another study found noincrease in protein kinase C activity in diabetic rats (approx-imate blood glucose, 17 mmol/liter) compared with controls(approximate blood glucose, 6.4 mmol/liter) (87). Support

for the possible role of the hexosamine pathway comes fromthe interesting observation that cerebral chitin, an N-acetyl-glucosamine polymer produced via the hexosamine path-way,is increased in human subjects withAlzheimers diseaseon autopsy (88). If hyperglycemia from diabetes shunts glu-cose toward the production of chitin, it is possible that theaccumulation of this molecule could contribute to abnormal-ities in cognition.

Hyperglycemia has also been proposed to cause end organdamage through increases in reactive oxygen species, in par-ticular superoxide, which could then lead to increased polyolpathway activation, increased formation of AGEs, activationof protein kinase C, and increased glucose shunting in the

hexosamine pathway (76). Using streptozotocin to inducediabetes in rats (blood glucose, 20.72 2.25 vs. 6.04 0.64mmol/liter in control rats), Aragno et al. (89) found thatRAGEs, galectin-3 (a proatherogenic molecule), and thepolyol pathway activation all were increased in rat brains,whereas activity of the glycolytic enzyme glyceradehyde-3-phosphate dehydrogenase was decreased, indicating ele-vated superoxide levels. Nuclear factor B transcription fac-tors, a proinflammatory gene marker up-regulated by AGEs,and S-100 protein, a marker for brain injury that can bind toRAGEs, were both up-regulated in the hippocampus in thisanimal model, although the effect in other regions was notassessed.Thesedata suggest that oxidative stress maytrigger

a cascade of events that lead to neuronal damage. Interest-ingly, dehydroepiandrosterone, an adrenal androgen andantioxidant, significantly reduces these changes, suggestinga potential therapy worthy of more investigation.

In addition to hyperglycemic-induced end organ damage,altered neurotransmitter function has been observed in di-abetic models and may also contribute to cognitive dysfunc-tion. In diabetic rats (blood glucose 28.6 1.1 vs. 6.3 0.2mmol/liter in control rats), there is an impairment of long-term potentiation, defined as activity-dependent prolongedenhancement of synaptic strength, in neurons rich in recep-tors for the neurotransmitter N-methyl-d-aspartate (NMDA),which could contribute to learning deficits (90). Other, neuro-chemical changes have been observed, including decreased

acetylcholine (91), decreased serotonin turnover, decreaseddopamine activity, and increased norepinephrine (86, 92) inthe brains of animals with diabetes. Interestingly,these changeswere all reversed with insulin. One proposed hypothesis is thatthe alternating high and low glucose levels seen in patientswith poorly controlled diabetes may worsen neurotransmitter

function (92).

B. The role of vascular disease

Patients with diabetes have a 2- to 6-fold increased risk inthrombotic stroke (41, 93), and vascular disease haslong beenhypothesized to contribute to abnormalities in cognition insuch patients. Autopsy studies on patients with long-stand-ing type 1 diabetes have shown changes related to vasculardisease, including diffuse brain degeneration, pseudocalci-nosis, demyelination of cranial nerves and spinal cord, andnerve fibrosis (94, 95). Thickening of capillary basement

membranes, the hallmark of diabetic microangiopathy, hasbeen found in the brains of patients with diabetes (96). Pa-tients with diabetes have also been found to have decreasedglobal rates of cerebral blood flow as measured using xenon,and the magnitude of reduction correlates with the durationof the disease. However, blood glucose levels were not con-trolled during the experiment (range, 3.121.2; mean, 8.8 4.74 mmol/liter) (97). Interestingly, the rate of cerebral bloodflow in patients with diabetes is similar to that found inAlzheimers patients with dementia (92). These observationsin humans with diabetes are supported by studies in strep-tozotocin-treated rats with chronic hyperglycemia (meanplasma glucose, approximately 29 mmol/liter) (98). One can

speculate that the decrease in cerebral blood flow, coupledwith the stimulation of the thromboxane A2 receptor knownto occur in patients with diabetes (92), could contribute to theinability of cerebral vessels to adequately vasodilate, whichmay in turn increase the likelihood of ischemia. The coex-istence of ischemia and hyperglycemia may be particularlydetrimental to the brain. Even modestly elevated blood glu-cose levels (greater than 8.6 mmol/liter) in humans duringa cerebrovascular event correlates with poorer clinical re-covery (99). One potential mechanism through which hy-perglycemia could potentiate ischemic damage is lactate ac-cumulation. Hyperglycemia provides more substrate forlactate to form, causing cellular acidosis and worsening in-

jury (93). Another mechanism is the accumulation of gluta-mate in the setting of hyperglycemia and ischemia (100).Glutamate, an excitatory amino acid neurotransmitter, has

been shown to cause neuronal damage in the brain (101).Although the exact mechanism is not known, the lack of

C-peptide in patients with type 1 diabetes may by itselfworsen cognitive impairment through its actions on the en-dothelium. Evidence for this is suggested by a rat model(blood glucose approximately 23 mmol/liter) in which re-placement of C-peptide to normal levels normalized cogni-tive function and reduced hippocampal apoptosis (102). Therelevance to humans is uncertain, however, because humanswith type 1 diabetes do not have hippocampal atrophy (103).




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C. The role of hypoglycemia

As mentioned in Section II.C, whether repeated episodes ofhypoglycemia contribute to cognitive dysfunction is contro-versial and most likely depends on the age of the patient.However, there is no argument that if severe hypoglycemialasts for a very long time, brain damage and death can occur

(93, 104106). Most endocrinologists have personal experi-ence with patients who have experienced severe hypogly-cemia(2 mm) with littleor no permanent consequence. Thismost likely is secondary to inaccuracies of glucometer at low

blood glucose levels (107), inadequate time with severe hy-poglycemia, or variations in patients glycogen stores. Thatsaid, ithas beenshown inanimalmodels thatafter 30 60 minof blood glucose levels between 0.12 and 1.36 mmol/liter,neuronal necrosis occurs with accompanying extracellularincreases in aspartate, alkalemia, and neuronal energy fail-ure, ultimately leading to a flat electroencephalograph (EEG)(105, 106). The cortex, basal ganglia, and hippocampus ap-pear to be most vulnerable to hypoglycemia, with laminar

necrosis and gliosis found in these regions on autopsies per-formed in human patients who died of hypoglycemia (104).Other human autopsy studies done after death secondary tohypoglycemia have shown multifocal or diffuse necrosis ofthe cerebral cortex and chromatolysis of ganglion cells (108).In animal models, hypoglycemia-induced damage seems to

be selective to neurons with sparing of astrocytes and oli-godendrocytes (92). Although counterintuitive, the time toneuronal death may be asymmetric between hemispheres insevere, prolonged hypoglycemia, making the differentiationof hypoglycemic brain damage from ischemia difficult on aclinical basis (105). Some have hypothesized that hypogly-cemia-induced neuronal damage occurs as a result of over-activation of a subtype of the excitatory neurotransmitterNMDA receptor (109). Interestingly, there exists an NMDAreceptor antagonist that has been shown to prevent neuronalnecrosis, suggesting a potential therapy for hypoglycemia-induced brain damage (110). Such a therapy may be helpfulin young children with type 1 diabetes who seem to beparticularly susceptible to cerebral complications of hypo-glycemia. There may also be a relationship to hypoglycemiaduring early nocturnal sleep, a time in which consolidationof memories occurs, and cognitive dysfunction. Comparedwith test outcomes after a night of sleep in euglycemia,human control subjects and subjects with type 1 diabetesexhibited impaired declarative memory (memory of facts)after undergoing a short, relatively mild hypoglycemic

clamp (2.2 mmol/liter) during early sleep (111). However, noneurocognitive deficits were seen in several other studies inwhich nocturnal hypoglycemia was induced later during thesleeping period (112, 113).

D. The role of insulin resistance and amyloid

Although the role of insulin on cerebral metabolism andfunction is still evolving, fascinating research has given usmore insight into this field over the last 20 yr. Historically,the brain was thought to be an insulin-independent organ;however, many recent discoveries have questioned that no-tion. Insulin receptors and mRNA expression have been

found to be widely distributed in rat brain using immuno-histochemistry and in situ hybridization (114, 115), respec-tively, including in the olfactory bulb, hypothalamus, hip-pocampus, cerebellum, piriform cortex, cerebral cortex, andamygdala. The insulin-responsive glucose transporter 4(GLUT4) has also been found in selectregions of therat brain,including the pituitary, hypothalamus, and medulla (116).GLUT8, also known as GLUTx1, is also found in the rat brain,specifically in the hippocampus, hypothalamus, cerebellum,and brainstem (117). GLUT8 has similar properties to GLUT4and is up-regulated in response to insulin in some (118) butnot all murine tissues, including the brain (119). Despite thepresence of insulin receptors and insulin-sensitive glucosetransporters, the effect of insulin on cerebral glucose metab-olism is still uncertain. Many laboratories, including ourown, have failed to demonstrate an effect of insulin on ce-rebral glucose metabolism in humans (120122). However,other laboratories using fluorodeoxyglucose positron emis-sion tomography (PET) have found a significant increase in

brain glucose metabolism in the setting of hyperinsulinemia

in humans (123), an effect that is reduced in subjects withperipheral insulin resistance (124). Despite the ongoing con-troversy of the effect of insulin on cerebral glucose metab-olism, there is a large and growing body of evidence thatinsulin resistance, long recognized as a factor contributing tothe onset of type 2 diabetes, may play a role in the patho-genesis of Alzheimers disease.

Theclinicaldiagnosis of Alzheimersdisease is made in thepresence of a significant gradual and progressive decline inmemory with at least one other cognitive, social, or occupa-tional disturbance (125). The incidence of Alzheimers dis-ease has been found to be approximately 1.2- to 1.7-foldhigher in patients with type 2 diabetes and insulin resistance

compared with a control population in most (3743, 47), butnot all (126128), investigations. The reason for the discrep-ancy could be the populations studied. Data that support arelationship between Alzheimers and insulin resistance allexamined older subjects ascertained from the general pop-ulation.The reports that failed to find an association collecteddata from a more narrowly defined population, such asthose with a high incidence of the apolipoprotein E type 4(APOE-4) allele (128) or a high percentage of early-onsetAlzheimers disease (126). Interestingly, it appears thattype 2 diabetes is also more common in populations withAlzheimers disease (129). Whether the association betweenAlzheimers disease and patients with type 2 diabetes reflects

the impact of poor metabolic control on brain function or theactual effects of insulin and insulin resistance on the brain isunclear. Patients with Alzheimers disease and normal glu-cose tolerance have a more robust insulin secretory responseto an oral glucose load than controls, suggesting that theymay have increased insulin resistance (130, 131). Some havesuggested that the insulin resistance occurs in the brain itselfand have hypothesized that the desensitization of neuronalinsulin receptors plays an important role in the developmentof sporadic Alzheimers disease (132). Such a concept is sup-ported by observations that patients with Alzheimers dis-ease have an elevated concentration of insulin in their cere-

bral spinal fluid under fasting conditions (131), along with anincrease in insulin receptor density in theoccipital region and




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a decrease in tyrosine kinase activity (which is downstreamto insulin binding) in the temporal and occipital lobes com-pared with controls (133). However, others have found thatpatients with Alzheimers disease have a decrease in cerebralspinal fluid insulin levels, suggesting that there may be im-paired insulin transport across the blood brain barrier orincreased insulin catabolism that accounts for the impairedcentral insulin action (134).

The mechanisms through which insulin resistance mightalter cognitive function remain uncertain, but effects on neu-rotransmission and memory formation have been hypothe-sized. An impairment in central cholinergic activity is be-lieved to contribute to the pathogenesis of Alzheimersdisease (135), and interestingly, rats with streptozotocin-induced diabetes have a decrease in the production andrelease of acetylcholine compared with control rats (91). Micemodels in which cholinergic activity is blocked by scopol-amine experience amnesia and hyperactivity, a deficit thatcan be reversed by glucose administration (136, 137). Glucoseadministration with a rise in endogenous insulin levels or

insulin administration to patients with Alzheimers diseasehave also been shown to alter behavior, perhaps by enhanc-ing cholinergic activity (138). In these studies, patients withAlzheimers demonstrated an improvement in declarativememory during either a hyperglycemic or a hyperinsuline-mic euglycemic clamp (138, 139). Furthermore, patients withmemory impairment and Alzheimers disease had improvedverbal memory acutely after intranasal insulin administra-tion, which had no effect on peripheral glucose or insulinlevels but had previously been shown to increase centralnervous system insulin levels (140). In addition to affectingcholinergic activity, diabetes and insulin may affect long-term potentiation in opposing ways. Long-term potentiation

is critical to the formation of memories and is induced byNMDA receptor activation, a process that is up-regulated inthe presence of insulin (141). However, rats with diabetes,and presumed relative insulin deficiency, have decreasedlong-term potentiations in the hippocampus as measured byelectrophysiology (90). As would be expected if long-termpotentiation were reduced, rat hippocampal neurons ex-posed to insulin exhibited inhibition of spontaneous firing(142). Interestingly, patients with Alzheimers disease havea reduced cerebral glucose uptake as measured by PET(143145) and have a reduced number of glucose transport-ers in the brain microvessels, frontal cortex, hippocampus,caudate nucleus, parietal, occipital, and temporal lobe com-

pared with controls on autopsy studies (146, 147). Perhapsthe reduction in glucose uptake has a direct effect on howinsulin regulates hippocampal function in these patients.Future experiments to identify the relative roles of glucoseand insulin in human cognition are necessary to clarify theserelationships.

The impact of insulin on cognitive function has also beenexamined in control subjects without Alzheimers disease ordiabetes mellitus. In our laboratory, we found that inducinghyperinsulinemia using an insulin infusion in control sub-

jects reduces parietal region P300 amplitude secondary tomemory triggers (148). Other clamp studies found improvedvigilance, memory, and selective attention in the setting ofhyperinsulinemia (149,150), whereas intranasal insulin treat-

ment for 8 wk improved delayed recall, enhanced mood, andself confidence and reduced anger in nondiabetic, nonde-mentia subjects (151). Based on these studies, it is hypothe-sized that in Alzheimers disease, cerebral insulin resis-tance requires higher levels of insulin to facilitate memory(46, 152). Although cerebral insulin is higher in these pa-

tients, it may not be enough to compensate for the insulinresistance. However, this does not necessarily prove thathyperinsulinemia directly improves cognitive function. Hy-perinsulinemia can stimulate epinephrine release, and bothinsulin and epinephrine have been shown to increase lactate(153). Lactate can then in turn be used as a source of energyin brain metabolism (154, 155), although the benefits of lac-tate therapy have not been proven to be beneficial yet inAlzheimers patients (156).

Insulin resistance and type 2 diabetes mellitus may con-tribute to cognitive dysfunction through three other indirectmechanisms. First, cognitive dysfunction in patients withtype 2 diabetes has been correlated to inflammatory markers,and increased inflammation may contribute to the develop-ment of Alzheimers or macrovascular disease. In one in-vestigation, patients with the metabolic syndrome, elevatedC-reactive protein, and elevated IL-6 were found to haveimpaired cognitive function, whereas those patients withthe metabolic syndrome and normal levels of these inflam-matory markers had similar cognition to controls (47). Pa-tients with type 2 diabetes are known to have higher levelsof inflammatory markers including C-reactive protein, -1-antichymotrypsin, IL-6, and intercellular adhesion mole-cule 1 than control populations (157). These findings raise thepossibility that insulin resistance and Alzheimers diseaseshare a common pathophysiology, because patients withAlzheimers disease demonstrate increased inflammatorymarkers as well (158, 159).

A second potential mechanism through which insulin re-sistance and type 2 diabetes could contribute to cognitivedysfunction is through the disruption of the hypothalamic-pituitary adrenal axis. Both animals (160) and humans (161)with type 2 diabetes have an up-regulation of the hypotha-lamic-pituitary-adrenal axis, with increased serum cortisolcompared withcontrols.In other research,hypercortisolemiahas been found to cause cognitive dysfunction. Healthy hu-mans treated with dexamethasone(162), corticosterone (163),and hydrocortisone (164) to mimic stress conditions all per-formed worse on memory testing. In a study of healthyelderly patients, those with higher serum cortisol levels per-formed more poorly on memory and attention testing (165).In addition, patients with Cushings disease have been foundto have worse performance on memory, attention, reasoning,and concept formation testing compared with controls (166),which may be attributed to a significant reduction in cerebralglucose metabolism found on PET scan in those patients withCushings disease (167). Supporting these findings are theanimal studies in which glucocorticoids cause structuraldamage and reduce function of neurons in the hippocampus(168172). Based on the facts that type 2 diabetes causes anup-regulation of the hypothalamic-pituitary-adrenal axisand hypercortisolemia can cause cognitive dysfunction, itcan be hypothesized that the increase in cortisol levels seen




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in patients with type 2 diabetes may contribute to cognitivedysfunction.

The third potential mechanism through which insulin re-sistance may indirectly contribute to cognitive dysfunctionis by promoting the formation of senile plaques found inAlzheimers disease. Intracellular neurofibrillary tangles andextracellular senile plaques composed of-amyloid are thepathological hallmarks of Alzheimers disease (173175).-Amyloid is formed from the cleavage of amyloid precursorprotein (APP), produced in neurons (176), by the enzymes- and -secretase (177). -Amyloid is eventually degraded

by the insulin-degrading enzyme (178, 179). Amyloid -peptides can by themselves bind to RAGEs and bring aboutmicroglial and neuronal dysfunction and oxidative stress(81). Interestingly, amyloid -peptides, AGEs, and RAGEshave all been colocalized in astrocytes using immunohisto-chemistry in human brain slices (180). In addition, there is agrowing body of evidence that insulin and insulin resistancecan affect the metabolism of APP and -amyloid, thus po-tentially increasing the burden of cerebral senile plaques.The

role of insulin resistance in the metabolism of APP and-amyloid was further clarified by Craft et al. (181). In theirexperiment, plasma levels of APP, the precursor to -amy-loid, were lower in those subjects with insulin resistance andAlzheimers disease when undergoing a hyperinsulinemic-euglycemic clamp. This corresponded with improved mem-ory testing. One potential explanation of this observation isthat insulin resistance may cause decreased APP degradationthat can be overcome by theelevating serum and presumablytissue insulin levels (181). Similar findings have come fromexperiments in rat hippocampal neurons, where insulin wasfound to up-regulate insulin degrading enzyme, thereby in-creasing-amyloiddegradation (182). However, not all stud-

ies have agreed with this hypothesis. In a study using neu-roblastoma cell lines by Gasparini et al. (178), insulin wasfound to decrease intracellular -amyloid and increase ex-tracellular levels of-amyloid by both promoting its secre-tion and inhibiting its degradation via the insulin-degradingenzyme. This would contradict the majority of the evidencethat insulin has a protective effect against memory loss.However, whereas it is widely believed that extracellularaccumulation of-amyloid plays a critical role in the devel-opment of Alzheimers, other evidence is suggesting there isa pathogenic role for intracellular -amyloid (183185). Moreresearch is needed concerning the pathophysiology of-amyloid and insulin before conclusions can be drawn.

Of interest is the observation that the pancreatic islets inpatients with type 2 diabetes mellitus are characterized by-cell loss and deposition of islet amyloid (186), which isreminiscent of the neuronal loss and -amyloid depositionseen in Alzheimers disease (187). The constitutions of isletand neural -amyloid are similar (129, 188), and both aretoxic to islet and neurons, respectively (189, 190). In a seriesof 29 patients in whom both brain and pancreas autopsyspecimens were available, all had amyloid detected to somedegreein both the brain and pancreas (187). In another study,islet amyloid was more abundantly present on autopsy inpatients with Alzheimers disease than in those withoutAlzheimers disease (129). Based on the similarity betweenislet and neural -amyloid, some have speculated that a

shared pathogenesis may be present in patients with type 2diabetes and patients with Alzheimers disease, possibly in-volving a defect in a chaperone protein (191) that helpsintracellular protein trafficking (129). Rat models of type 2diabetes (BBZDR/Wor), even more so than type 1 (BB/Wor)diabetes, demonstrate an increase in Alzheimers pathology,including increased APP, -amyloid, and -secretase andloss of neurons (192). Despite this compelling evidence link-ing insulin resistance and type 2 diabetes mellitus to Alz-heimers disease and pathology, several autopsy studies per-formed in humans have failed to identify an increase in senileplaques or neurofibrillary tangles in subjects with diabetescompared with age-matched controls (83, 129), although theduration of diabetes did correlate with the density of senileplaques in one of these studies (129).

The relationship between insulin resistance and cognitivedysfunction in Alzheimers disease appears to depend on thepresence or absence of the APOE-4 allele. Curiously, al-though the presence of the APOE-4 allele is associated withan increased incidence of Alzheimers disease (193), it seems

that insulin resistance is only a significant risk factor forAlzheimers disease in those patients without the APOE-4allele (39, 134). Patients with Alzheimers disease and noAPOE-4 allele have been observed to have lower glucosedisposal rates during a hyperinsulinemic-euglycemic clampthan subjects with Alzheimers disease and the APOE-4allele, as well as those subjects without Alzheimers diseaseor the APOE-4 allele. Subjects with Alzheimers diseasewithout the APOE-4 allele also had improved memoryscores in the setting of hyperinsulinemia, which was not thecase in APOE-4 allele-positive subjects (149, 181). Based onthis information, it seems that insulin resistance/type 2 di-abetes and APOE-4 allele positivity are distinct and separate

risk factors for the development of Alzheimers disease, ahypothesis that is supported by the fact that those withdiabetes had a low incidence of the APOE-4 allele (128).However, there is again a contradiction in the literature; inthe Honolulu-Asia Aging Study, those subjects with bothtype 2 diabetes and the APOE-4 allele had an additiveincreased risk of dementia and Alzheimers pathology (43).This study was specific for elderly Japanese-American men,so it seems that additional multiethnic studies are needed tounderstand this discrepancy better.

The association between insulin resistance and Alzheimersdisease has been sufficiently compelling for investigatorsto examine whether peroxisome proliferator-activated

receptor- (PPAR-) agonists can treat Alzheimers diseasein the absence of diabetes. To date, two trials have demon-strated rosiglitazone to have a beneficial effect on memory inpatients with Alzheimers disease. In a small randomizedstudy published by Watson et al. (194) in 2005, patients withmild Alzheimers disease treated for 6 months with rosigli-tazone had better memory and selective attention than con-trols. A much larger study published in 2006 found thatpatients with Alzheimers disease without the APOE-4 al-lele had improvements in cognitive testing after 6 months ofrosiglitazone, whereas those Alzheimers disease patientswith the APOE-4 allele did not have improvements (195).Multiple mechanisms have been proposed to address howPPAR-agonists may affect the pathophysiology responsible




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for Alzheimers disease, including reducing serum glucocorti-coids (196), decreasing glial inflammation (197, 198), protectingagainst -amyloid-induced neurodegeneration (199), decreas-ing -amyloid production (197), increasing -amyloid degra-dation (196, 200), and decreasing phosphorylation of tau pro-teins, the mechanism by which neurofibrillary tangles areformed (201). Interestingly, despite all of these data, it is stillnot totally clear how rosiglitazone benefited patients withAlzheimers disease in clinical trials because it has been shownnot to cross the blood-brain barrier (196). These data are com-pelling enough to warrant further, longer-term studies on the

benefits of PPAR- agonists in the treatment of Alzheimersdisease. However, clinicians must weight the benefits againstthe newly documented cardiovascular risks of these treatments(202, 203).

IV. Modalities for Assessment of Cognitive

Dysfunction in Patients with Diabetes

Although progress is being made, the difficulty of detect-ing neurocognitive dysfunction in patients with diabetes inthe clinical setting may explain in part why the field ofcognitive dysfunction in diabetes has not advanced similarlyto other fields dealing with hyperglycemia-associated endorgan damage. Neurocognitive testing in which an examineradministers a battery of tests to assess different aspects ofcerebral function has long been the gold standard for theassessment of neurocognitive function. Although cumber-some to administer and score, it has been very useful inassessing neurocognition in a variety of disease states, in-cluding diabetes, as was demonstrated in Section II. How-ever, such tests have a relatively high rate of intrasubject

variability that reduces their ability to identify mild deficitsor preclinical disease. Also, many studies examining theeffect of diabetes on brain function use multiple neurocog-nitive tests that assess the same psychological process. Whenthe results of these different tests dont agree, determiningwhich results to base conclusions on can be confusing (204).In addition, not all neurocognitive tests are created equal.Although many neurocognitive tests are well validated in adiverse population to distinguish between normal andabnormal results, other tests do not have adequate reli-ability data, are based on unacceptably small norms, areadministered inappropriately, or do not properly distinguish

between two or more diagnostic groups (205). Finally, neu-

rocognitive testing is unable to provide specific informationabout the neural structures responsible for any dysfunctionidentified. For example, although it appears that white mat-ter function such as processing speed, attention, and visual-spatial processing are particularly affected by diabetes (4),localization of this dysfunction to white or gray matter is notpossible using the battery of tests available to assessneurocognition.

Because of the limitations in neurocognitive testing, anumber of modalities have been used to assess cognitivefunction in patients with diabetes (Table 3). One of the oldestmodalities has been to measure electrical activity such asevoked response potentials in the brain after the adminis-tration of different stimuli. Abnormal evoked response po-

tentials can reveal subclinical sensory nerve conduction def-icits that may not otherwise be apparent (206). For example,flash electroretinography has shown decreased potentialsfrom the retina in diabetic subjects before ophthalmoscopicsigns of retinopathy were seen (108). In addition, patternelectroretinogram, which looks at the pattern of retinal stim-uli originating from the ganglion cells, is also decreased inpatients with diabetes (108). The evoked response of nervesinvolved in sensing auditory stimuli is also abnormal; brain-stem auditory-evoked potentials demonstrated acoustic

pathway impairment in patients with diabetes (207209).Evoked potentials related to memory may also be affected

because auditory P300 event-related potentials had signifi-cantly longer latencies in patients with type 2 diabetes com-pared with controls, which could relate to attention andshort-term memory defects (210). Central somatosensory-evoked potentials were found to be prolonged in patientswith diabetes as well (211). In another study looking at bothtype 1 and type 2 diabetes, slowed latency in visual andsomatosensory-evoked potentials was observed in patientswith type 1 diabetes, whereas patients with type 2 diabeteshad slowed latency of visual, somatosensory, and brainstemauditory-evoked potentials (212). In this investigation, in-

creasing HbA1c was related to reduced cognitive perfor-mance. Event-related potentials have also helped define

brain adaptations to hypoglycemia. During hypoglycemia,normal subjects do not experience a delay in initial percep-tion and precognitive processing, but they do have a delayin central processes such as stimulus selection and selectivecentral motor activation (213). Of note, although all exceptone of these studies controlled for hypoglycemia duringtesting (211), none of the studies adequately controlled forhyperglycemia during testing, although Kurita et al. (210)found no difference between those subjects with high andrelatively normal blood glucose values.

EEG can also assess spontaneous cerebral electrical activ-

ity and has been used in patients with type 1 and type 2diabetes. Patients with type 2 diabetes have been found tohave slowing in the EEG frequency band analysis over thecentral cortex area and reduction of alpha activity over theparietal area. These findings correlated with reduced visualretention on neurocognitive testing but were not simply re-lated to hyperglycemia because making nondiabetic subjectswith hyperglycemia did not reproduce these findings (32).Subjects with type 1 diabetes have also been found to haveabnormal EEG results compared with controls, with thosepatients with a history of having severe hypoglycemia hav-ing the most abnormalities (65, 214, 215).

Magnetic resonance imaging (MRI) has been used in anumber of studies to examine cerebral structure in patients

TABLE 3. Summary of modalities for assessment of cognitivedysfunction in patients with diabetes

Neurocognitive testingEvoked response potentialsEEGMRIfMRI

SPECTPET




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with type 1 and type 2 diabetes and has pretty consistentlyfound the brains of such subjects to have leukoariosis, whichare hyperintense white matter lesions (207, 216). One studyfound that 69% of middle-aged adults with long-standingtype 1 diabetes had abnormal MRI scans, compared with 12%of healthy, aged-matched volunteers, with an increasednumber of larger, high-signal lesions in the cerebrum, cer-ebellum, andbrain stem being theprimary abnormality iden-tified (207). However, this was not confirmed by a morerecent published study in which relatively young patients(2540 yr old) with type 1 diabetes for more than 15 yr didnot have a significant difference in white matter hyperin-tensities compared with healthy controls. In addition, whitematter hyperintensities did not correlate with depressivehistory, retinopathy, severe hypoglycemia, glycemia control,and most neurocognitive tests (with the exception of delayedmemory) (7). This is in agreement with previous studies(3, 217). The reason for the discrepancy may have been thatsubjects in the former study had more severe microvascularcomplications and that differences in cardiovascular risk fac-

tors between subjects with diabetes and controls were notcontrolled for. In patients with type 2 diabetes, these whitematter hyperintensities have been noted to correlate withreduced performance on tests of attention, executive func-tion, information processing speed, and memory (216, 218).The nature of these white matter lesions is uncertain, butinvestigators have hypothesized that they could representdemyelination, increased water content, angionecrosis, cys-tic infarcts, or gliosis (i.e. brain tissue scarring) (92).

MRI has also demonstrated that subjects with type 2 di-abetes have hippocampal and amygdala atrophy relative tocontrol subjects (219). The hippocampus and amygdala areresponsible for such functions as memory and behavior and,

interestingly, are also found to be atrophied in Alzheimerspatients (219). However, a similar study in subjects with type1 diabetes failed to identify reductions in hippocampal andamygdala volume, although these subjects did have an in-crease in cerebrospinal fluid on MRI, suggesting mild globalcerebral atrophy (103). Another study compared MRI find-ings and neuropsychometric testing in patients with an earlyage ofonsetof type1 diabetes(younger than age 7) and a laterage of onset (717 yr old). Subjects with early onset diseasehad larger ventricular volumes and more prevalent ventric-ular atrophy than those with later onset,whichcorrespondedto poorer intellectual and information processing ability (220).Atrophy in subcortical and periventricular areas has also been

associated with reduced performance on memory tasks in pa-tients with type 2 diabetes (216). A history of hypoglycemiaappears to be related to an increase in cerebral atrophy (70).

Recently, voxel-based morphometry, in which differencesin local characteristics of tissue are measured using MRI, has

been used to evaluate both the gray and white matter ofpatients with type 1 diabetes. Musen et al. (221) found thatcompared with controls, patients with type 1 diabetes hadlower gray matter density in certain areas of the temporallobe, frontal lobe, and thalamus. They also found that higherHbA1c levels correlated with lower gray matter density inareas important for language, memory, and attention,whereas a history of severe hypoglycemia correlated withless gray matter density in the left cerebellar posterior lobe

(221). Wessels et al. (222) performed a similar experiment butcompared patients with type 1 diabetes and retinopathy,patients with type 1 diabetes and no retinopathy, and con-trols. They found that patients with type 1 diabetes andproliferative retinopathy had decreased gray matter densityin the right inferior gyrus and right occipital lobe comparedwith those patients with diabetes and no retinopathy, as wellas to controls. More recently, Wessels and colleagues appliedvoxel-based morphometry to white matter volumes. Theyfound that those subjects with type 1 diabetes and prolifer-ative retinopathy had significantly smaller white matter vol-ume than subjects without diabetes, and that smaller whitematter volume correlated with worse performances on at-tention, speed of information processing, and executive func-tion. This was not seen in patients with type 1 diabetes whohad no proliferative retinopathy, suggesting a possible com-mon mechanism in the development of retinopathy and ce-rebral dysfunction (6). Preliminary findings by Perantie et al.(223) have found that a history of severe hypoglycemia inchildren is associated with decreased gray matter in the left

superior temporal region, whereas increased HbAlc levelsare associated with reductions of gray matter in the rightcuneus and precuneus regions, reductions of white matter inthe right posterior parietal region, and increased gray matterin the right prefrontal cortex.

Functional MRI (fMRI) has also been used to assess cere-bral function in patients with diabetes. fMRI is based on thefact that increases in cerebral blood flow and metabolismduring stimulus-induced neuronal activation are accompa-nied by a relative reduction in deoxyhemoglobin content ofthe activated tissue relative to the adjacent unactivated brain.Because deoxyhemoglobin is a paramagnetic molecule, it can

be visualized by MRI. Rosenthal et al. (224) applied fMRI to

the study of cerebral function during standard neurocogni-tive testing in subjects with type 1 diabetes subjected to botheuglycemia and hypoglycemia. They found that the effect ofacute hypoglycemia on cerebral blood flow is task and regionspecific. For example, during hypoglycemia, the slower fin-ger tapping corresponded to decreased activation of the rightpremotor cortex, supplementary motor area, and left hip-pocampus and with increased activation in the left cerebel-lum and right frontal pole. In addition, during hypoglycemiadeterioration of four-choice reaction time correlated withreduced activation in the motor and visual systems but withincreased activation of the part of the parietalcortex involvedin planning (224). More recently, Wessels et al. (24) applied

this methodology to determine whether subjects with type 1diabetes with known hyperglycemia-induced end organdamage, specifically retinopathy, had differing areas of ce-rebral activation with cognitive stimuli and hypoglycemiacompared with patients with type 1 diabetes and no micro-vascular complications. Although there was no differenceseen in cognitive ability between the two groups, there wasan overall increase in activation and less appropriate deac-tivation of certain brain regions during hypoglycemia in thediabetic group with retinopathy. The investigators hypoth-esized that regional alterations in activation were secondaryto hyperglycemia-induced end organ damage in the centralnervous system, causing altered neurovascular coupling orfunctional microvascular alterations (24). Preliminary find-




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ings by Musen et al. (225) have found decreased activation inthe superior temporal gyrus and the parahippocampal gyrusin response to lexical and recognition stimuli, respectively, ina group composed of patients with long-standing type 1diabetes compared with controls.

Other imaging modalities such as single photon emissioncomputed tomography (SPECT) and PET have been used toassess cerebral function in patients with diabetes mellitus.SPECT is particularly good at assessing cerebral perfusionand has demonstrated in an uncontrolled study that patientswith type 2 diabetes and dementia have a high incidence ofhypoperfusion in at least one area of the brain (226). How-ever, SPECT has also demonstrated that patients with type1 diabetes have hyperperfusion in the prefrontal and frontal

brain regions compared with controls (227). Other investi-gators found that when the SPECT data are corrected for theincrease in cerebral atrophy seen in patients with diabetes,cerebral blood flow and glucose metabolism values werewithin normal range (228). PET with fluorodeoxyglucose isa technique that can be used to assess glucose metabolism

because the compound is taken up and trapped in the cell byphosphorylation. When this method was used in patientswith type 1 diabetes and a history of severe hypoglycemiaand hypoglycemia unawareness, no differences in glucosemetabolism were found relative to controls, although neu-ropsychological testing was also not significantly different(69). Two pilot studies, one by our own laboratory, haveused diffusion tensor imaging, a type of MRI that mea-sures white matter integrity quantitatively by fractionalanisotropy (229, 230), in patients with diabetes. Prelimi-nary findings show a reduction in white matter integrityin patients with type 1 diabetes that was associated withseverity of hyperglycemia (231) and poorer performance

on certain neurocognitive tests (67).In general, assessment modalities to detect cognitive dys-

function associated with diabetes have been disappointing.Neurocognitive testing is cumbersome and lacks pathophys-iological insight. Evoked response potentials and EEG seemto be good at detecting sensory/perception deficits but arealso cumbersome and do not provide as much informationabout more complex cognitive functions. Although promis-ing, there have been conflicting results with regard to MRIstudies, specifically in patients with type 1 diabetes. Theutility of SPECT, PET, and diffusion tensor imaging in mon-itoring or detecting changes in patients with cognitive dys-function and diabetes remains to be determined.

V. Future Directions

Although much research has been done on the impact ofdiabetes mellitus on cognitive function, many questions stillremain. It is clear that patients with type1 and type2 diabeteshave been found to have abnormalities in neurocognitivefunction, although the natural history and clinical signifi-cance of these findings have not yet been clearly defined. Forexample, we know that there is an increased incidence ofdementia in patients with type 2 diabetes (37, 38, 40 44), butwe do not know whether the more subtle changes in memoryand in other measures on neurocognitive testing are a pre-

cursorto true dementia or representanother process. We alsodo not know whether the incidence of dementia is increasedin patients with type 1 diabetes compared with the rest of thepopulation. In prior decades, this was not an issue becausepatients with type 1 diabetes died at relatively young agesfrom other complications of the disease. However, now thatpatients with type 1 diabetes are livinglonger and better withthe disease, this must be assessed. Finally, it is not clearwhether the subtle cognitive deficits identified in many stud-ies truly impact the lives of patients living with diabetes (34).Future studies, perhaps longitudinal in nature or involving

better serum/imaging biomarkers, will be of tremendousbenefit in providing better understanding of the natural his-tory of this complication.

Future study will also be important in understanding thepathogenesis of cognitive dysfunction secondary to diabetes.Although it seems that hyperglycemia and hyperglycemia-induced end organ damage contribute to this problem, theactual mechanisms through which hyperglycemia alters ce-rebral structure and function are not clear. Improved glyce-

mic control is likely of therapeutic benefit, as has been sug-gested by many retrospective studies (5, 1518, 2628, 48),

but a prospective study is needed to determine whether thisis true. In addition, identification of the mechanisms throughwhich hyperglycemia may impair cognitive function in pa-tients with diabetes will stimulate new research into ways toprevent and treat all of the hyperglycemia-associated com-plications of diabetes.

VI. Conclusion

In conclusion, there have been significant gains in ourunderstanding of the effect of diabetes on cognitive dys-function. Evidence from neurocognitive testing suggests thatcognitive dysfunction should be listed as one of the manycomplications of diabetes, along with retinopathy, neurop-athy, nephropathy, and cardiovascular disease. The patho-genesis of cognitive dysfunction is onlypartially understood.Although many studies suggest that changes in cerebralstructure and function in diabetes are related to hypergly-cemia-induced end organ damage, macrovascular disease,hypoglycemia, insulin resistance, and amyloid lesions mayplay a role in some patients. Greater understanding of thenatural history of this diabetes complication and the mech-anisms responsible for its development will continue to ad-vance as biochemical and imaging modalities continue to

evolve. As new knowledge is gained, it can be applied todevelop new and improved ways to prevent and treat all ofthe hyperglycemia-related complications of diabetes.

Acknowledgments

Received October 1, 2007. Accepted March 28, 2008.Address all correspondence and requests for reprints to: Elizabeth R.

Seaquist,M. D., Departmentof Medicine,Division of EndocrinologyandDiabetes, University of Minnesota, Campus Delivery Code 1932, Suite229, 717 Delaware Street SE, Minneapolis, Minnesota 55414. E-mail:[email protected]

This work was supported by NIH Grants NS35192 (to E.R.S.),DK62440 (to E.R.S.), and 2 T32 DK00720329A1 (to C.T.K.).




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Disclosure Statement: E.R.S. has served on advisory boards for Pfizerand Merck. C.T.K. has no disclosures to state.

References

1. 2003 U.S. Renal Data System (USRDS) Annual Data Report: Atlasof end-stage renal disease in the United States. Bethesda, MD:

National Institutes of Health, National Institute of Diabetes andDigestive and Kidney Diseases

2. Miles WR, Root HF 1922 Psychologic tests applied to diabeticpatients. Arch Intern Med 30:767777

3. Brands AM, Kessels RP, Hoogma RP, Henselmans JM, van derBeek Boter JW, Kappelle LJ, de Haan EH, Biessels GJ 2006 Cog-nitive performance, psychological well-being, and brain magneticresonance imaging in older patients with type 1 diabetes. Diabetes55:18001806

4. Ryan CM, Geckle MO, Orchard TJ 2003 Cognitive efficiency de-clines over time in adults with type 1 diabetes: effects of micro-andmacrovascular complications. Diabetologia 46:940948

5. RyanCM, WilliamsTM, FinegoldDN, OrchardTJ1993 Cognitivedysfunction in adults with type 1 (insulin-dependent) diabetesmellitus of long duration: effects of recurrent hypoglycaemia andother chronic complications. Diabetologia 36:329334

6. Wessels AM, Rombouts SA, Remijnse PL, Boom Y, Scheltens P,Barkhof F, Heine RJ, Snoek FJ 2007 Cognitive performance in type1 diabetes patients is associatedwith cerebral white mattervolume.Diabetologia 20:17631769

7. Weinger K, Jacobson AM,MusenG, Lyoo IK,Ryan CM, JimersonDC, Renshaw PF 2008 The effects of type 1 diabetes on cerebralwhite matter. Diabetologia 51:417425

8. Hershey T, Bhargava N, Sadler M, White NH, Craft S 1999 Con-ventional versus intensive diabetes therapy in children with type1 diabetes: effects on memory and motor speed. Diabetes Care22:13181324

9. Ryan CM 1988 Neurobehavioral complications of type I diabetes.Examination of possible risk factors. Diabetes Care 11:8693

10. Skenazy JA, Bigler ED 1984 Neuropsychological findings in dia-betes mellitus. J Clin Psychol 40:246 258

11. Hershey T, Craft S, Bhargava N, White NH 1997 Memory and

insulin dependent diabetes mellitus (IDDM): effects of childhoodonset and severe hypoglycemia. J Int Neuropsychol Soc 3:50952012. Northam EA, Anderson PJ, Werther GA, Warne GL, Adler RG,

Andrewes D 1998 Neuropsychological complications of IDDM inchildren 2 years after disease onset. Diabetes Care 21:379384

13. Schoenle EJ, Schoenle D, Molinari L, Largo RH 2002 Impairedintellectual development in children with type I diabetes: associ-ation with HbA(1c), age at diagnosis and sex. Diabetologia 45:108114

14. Northam EA, Anderson PJ, Jacobs R, Hughes M, Warne GL,Werther GA 2001 Neuropsychological profiles of children withtype 1 diabetes 6 years after disease onset. Diabetes Care 24:15411546

15. JacobsonAM, Musen G, Ryan CM,Silvers N, Cleary P, WaberskiB, Burwood A, Weinger K, Bayless M, Dahms W, Harth J 2007Long-term effect of diabetes and its treatment on cognitive func-

tion. N Engl J Med 356:1842185216. Holmes CS 1986 Neuropsychological profiles in men with insulin-dependent diabetes. J Consult Clin Psychol 54:386389

17. Kaufman FR, Epport K, Engilman R, Halvorson M 1999 Neuro-cognitive functioning in children diagnosed with diabetes beforeage 10 years. J Diabetes Complications 13:3138

18. PerantieDC, LimA, WuJ, WeaverP, WarrenSL,HaydenT, ChristS, Sadler M, White NH, Hershey T 2007 Severe hypoglycemia vs.hyperglycemia: unique effects on cognition in youth with type 1diabetes mellitus (TIDM). Diabetes 56(Suppl 1):(Abstract 1887)

19. Cox DJ, Kovatchev BP, Gonder-Frederick LA, Summers KH,McCall A, Grimm KJ, Clarke WL 2005 Relationships betweenhyperglycemia and cognitive performance amongadults with type1 and type 2 diabetes. Diabetes Care 28:7177

20. Rovet J, Alvarez M 1997 Attentional functioning in children andadolescents with IDDM. Diabetes Care 20:803810

21. Sommerfield AJ, Deary IJ, Frier BM 2004 Acute hyperglycemia

alters moodstate and impairs cognitiveperformance in people withtype 2 diabetes. Diabetes Care 27:23352340

22. Brands AM, Biessels GJ, de Haan EH, Kappelle LJ, Kessels RP2005 The effects of type 1 diabetes on cognitive performance: ameta-analysis. Diabetes Care 28:726735

23. Ferguson SC,Blane A, PerrosP, McCrimmon RJ, Best JJ,WardlawJ, Deary IJ, Frier BM 2003 Cognitive ability and brain structure intype 1 diabetes: relation to microangiopathy and preceding severe

hypoglycemia. Diabetes 52:14915624. Wessels AM, Rombouts SA, Simsek S, Kuijer JP, Kostense PJ,

Barkhof F, Scheltens P, Snoek FJ, Heine RJ 2006 Microvasculardisease in type 1 diabetes alters brain activation: a functional mag-netic resonance imaging study. Diabetes 55:334340

25. Gregg EW, Yaffe K, CauleyJA, Rolka DB,Blackwell TL, NarayanKM, Cummings SR 2000 Is diabetes associated with cognitiveimpairment and cognitive decline among older women? Study ofOsteoporotic Fractures Research Group. Arch Intern Med 160:174180

26. Reaven GM, Thompson LW, Nahum D, Haskins E 1990 Rela-tionship between hyperglycemia and cognitive function in olderNIDDM patients. Diabetes Care 13:1621

27. Munshi M, Grande L, Hayes M, Ayres D, Suhl E, CapelsonR, LinS, Milberg W, WeingerK 2006 Cognitive dysfunction is associatedwith poor diabetes control in older adults. Diabetes Care 29:1794

179928. Perlmuter LC, Hakami MK, Hodgson-Harrington C, Ginsberg J,

Katz J, Singer DE, Nathan DM 1984 Decreased cognitive functionin aging non-insulin-dependent diabetic patients. Am J Med 77:10431048

29. Messier C 2005 Impact of impaired glucose tolerance and type 2diabetes on cognitive aging. Neurobiol Aging 26(Suppl 1):2630

30. Grodstein F, Chen J, Wilson RS, Manson JE 2001 Type 2 diabetesand cognitive function in community-dwelling elderly women.Diabetes Care 24:10601065

31. Kanaya AM, Barrett-Connor E, Gildengorin G, Yaffe K 2004Change in cognitive function by glucose tolerance status in olderadults: a 4-year prospective study of the Rancho Bernardo studycohort. Arch Intern Med 164:13271333

32. Mooradian AD, Perryman K, Fitten J, Kavonian GD, Morley JE1988 Cortical function in elderly non-insulin dependent diabetic

patients. Behavioral and electrophysiologic studies. Arch InternMed 148:23692372

33. Fontbonne A, Berr C, DucimetiereP, Alperovitch A2001 Changesin cognitive abilities over a 4-year period are unfavorably affectedin elderly diabetic subjects: results of the Epidemiologyof VascularAging Study. Diabetes Care 24:366370

34. Sinclair AJ, Girling AJ, Bayer AJ 2000 Cognitive dysfunction inolder subjects with diabetes mellitus: impact on diabetes self-management and use of care services. All Wales Research intoElderly (AWARE) Study. Diabetes Res Clin Pract 50:203212

35. Gregg EW,BrownAM 2003Cognitiveand physical disabilitiesandaging-related complications of diabetes. Clin Diabetes 21:113118

36. Bruce DG, Casey GP, Grange V, Clarnette RC, Almeida OP,Foster JK, Ives FJ, Davis TM 2003 Cognitive impairment, physicaldisability and depressive symptoms in older diabetic patients: theFremantle Cognition in Diabetes Study. Diabetes Res Clin Pract

61:596737. CukiermanT, Gerstein HC, WilliamsonJD2005 Cognitive decline

and dementia in diabetessystematic overview of prospective ob-servational studies. Diabetologia 48:24602469

38. Curb JD, Rodriguez BL, Abbott RD, Petrovitch H, Ross GW,Masaki KH, Foley D, Blanchette PL, Harris T, Chen R, White LR1999 Longitudinal association of vascular and Alzheimers demen-tias, diabetes, and glucose tolerance. Neurology 52:971975

39. Kuusisto J, Koivisto K, Mykkanen L, Helkala EL, Vanhanen M,Hanninen T, Kervinen K, Kesaniemi YA, Riekkinen PJ, LaaksoM 1997 Association between features of the insulin resistance syn-drome and Alzheimers disease independently of apolipoproteinE4 phenotype: cross-sectional population based study. BMJ 315:10451049

40. Leibson CL, Rocca WA, Hanson VA, Cha R, Kokmen E, OBrienPC, Palumbo PJ 1997 Risk of dementia among persons with dia-




14/18

betes mellitus: a population-based cohort study. Am J Epidemiol145:301308

41. Luchsinger JA, Tang MX, Stern Y, Shea S, Mayeux R 2001 Dia-betes mellitus and risk of Alzheimers disease and dementia withstroke in a multiethnic cohort. Am J Epidemiol 154:635 641

42. Ott A, Stolk RP, Hofman A, van Harskamp F, Grobbee DE,Breteler MM 1996 Association of diabetes mellitus and dementia:the Rotterdam Study. Diabetologia 39:13921397

43. Peila R, Rodriguez BL, Launer LJ 2002 Type 2 diabetes, APOEgene, and the risk for dementia and related pathologies: theHonolulu-Asia Aging Study. Diabetes 51:12561262

44. Sullivan MG, Glycemic control shown to prevent dementia. 10thInternational Conference on Alzheimers Disease and Related Dis-orders, Madrid, Spain, 2006

45. YoshitakeT, Kiyohara Y, Kato I, OhmuraT, Iwamoto H, Nakayama K,Ohmori S, Nomiyama K, Kawano H, Ueda K, Sueshi K, TsuneyoshiM,FujishimaM 1995IncidenceandriskfactorsofvasculardementiaandAlzheimers disease in a defined elderly Japanese population: the Hi-sayama Study. Neurology 45:11611168

46. Watson GS, Craft S 2003 The role of insulin resistance in thepathogenesis of Alzheimers disease: implications for treatment.CNS Drugs 17:2745

47. Yaffe K, Blackwell T, Whitmer RA, Krueger K, Barrett Connor E2006 Glycosylated hemoglobin level and development of mild cog-

nitive impairment or dementia in older women. J Nutr HealthAging 10:29329548. Ryan CM, Geckle MO 2000 Circumscribed cognitive dysfunction

in middle-aged adults with type 2 diabetes.Diabetes Care 23:14861493

49. Vanhanen M, Koivisto K, Kuusisto J, Mykkanen L, Helkala EL,Hanninen T, Riekkinen Sr P, Soininen H, Laakso M 1998 Cog-nitive function in an elderly population with persistent impairedglucose tolerance. Diabetes Care 21:398 402

50. de Vegt F, Dekker JM, Ruhe HG, Stehouwer CD, Nijpels G,Bouter LM, Heine RJ 1999 Hyperglycaemia is associated withall-causeand cardiovascularmortalityin the Hoorn population: theHoorn Study. Diabetologia 42:926931

51. Dilley J, Ganesan A, Deepa R, Deepa M, Sharada G, WilliamsOD,MohanV 2007Association of A1C with cardiovasculardiseaseand metabolic syndrome in Asian Indians with normal glucose

tolerance. Diabetes Care 30:1527153252. Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N2004 Association of hemoglobin A1c with cardiovascular diseaseand mortality in adults: the European prospective investigationinto cancer in Norfolk. Ann Intern Med 141:413 420

53. Kumari M, Marmot M 2005 Diabetes and cognitive function in amiddle-aged cohort: findings from the Whitehall II study. Neu-rology 65:15971603

54. Scott RD, Kritz-Silverstein D, Barrett-Connor E, Wiederholt WC1998 The association of non-insulin-dependent diabetes mellitusand cognitive function in an older cohort. J Am Geriatr Soc 46:12171222

55. L

cognitive dysfunction and diabetes mellitus

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