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1 Epidemiology/Health Servies Researh O R I G I N A L A R T I C L E Assoiation of Metaboli Dysregulation With Volumetri Brain Magneti Resonane Imaging and Cognitive Markers of Sublinial Brain Aging in Middle-Aged Adults The Framingham Offspring Study ZALDY S. TAN, MD, MH 1,2,3,4 ALEXA S. BEISER, HD 4,5,6 CAROLINE S. FOX, MD, MH 3,4,7 RHODA AU, HD 4,5 JAYANDRA J. HIMALI, MS 4,6 STEHANIE DEBETTE, MD 5 CHARLES DECARLI, MD 8 RAMACHANDRAN S. VASAN, MD 4,9 HILI A. WOLF, MD 4,5 SUDHA SESHADRI, MD 4,5 OBJECTIVE Diabeti and prediabti states, inluding insulin resistane, fasting hyperglyemia, and hyperinsulinemia, are assoiated with metaboli dysregulation. These omponents have been individually linked to inreased risks of ognitive deline and Alzheimer s disease.we aimed to omprehensively relate all of the omponents of metaboli dysregulation to ognitive funtion and brain magneti resonane imaging (MRI) in middle-aged adults. RESEARCH DESIGN AND METHODS Framingham Offspring partiipants who underwent volumetri MRI and detailed ognitive testing and were free of linial stroke and dementia during examination 7 ( ) onstituted our study sample (n = 2,439; 1,311 women; age years). We related diabetes, homeostasis model assessment of insulin resistane (HOMA-IR), fasting insulin, and glyohemoglobin levels to ross-setional MRI measures of total erebral brain volume (TCBV) and hippoampal volume and to verbal and visuospatial memory and exeutive funtion. We serially adjusted for age, sex, and eduation alone (model A), additionally for other vasular risk fators (model B), and finally, with the inlusion of apolipoprotein E- 4, plasma homoysteine, C-reative protein, and interleukin-6 (model C). RESULTS We observed an inverse assoiation between all indies of metaboli dysfuntion and TCBV in all models (, 0.030). The observed differene in TCBV between partiipants with and without diabetes was equivalent to approximately 6 years of hronologi aging. Diabetes and elevated glyohemoglobin, HOMA-IR, and fasting insulin were related to poorer exeutive funtion sores (, 0.038), whereas only HOMA-IR and fasting insulin were inversely related to visuospatial memory (, 0.007). CONCLUSIONS Metaboli dysregulation, espeially insulin resistane, was assoiated with lower brain volumes and exeutive funtion in a large, relatively healthy, middle-aged, ommunity-based ohort. Diabetes Care 34: , 2011 From the 1 Geriatri Researh Eduation and Clinial Center, Veterans Administration Boston Healthare System, Boston, Massahusetts; the 2 Department of Mediine, Division of Aging, Brigham and Women s Hospital, Boston, Massahusetts; 3 Harvard Medial Shool, Boston, Massahusetts; the 4 National Heart, Lung, and Blood Institute s Framingham Heart Study, Framingham, Massahusetts; the 5 Department of Neurology, Boston University Shool of Mediine, Boston, Massahusetts; the 6 Department of Biostatistis, Boston University Shool of ubli Health, Boston, Massahusetts; the 7 Department of Mediine, Division of Endorinology, Hypertension and Metabolism, Brigham and Women s Hospital, Boston, Massahusetts; the 8 Department of Neurology, University of California Davis, Davis, California; and the 9 Department of Mediine, Boston University Shool of Mediine, Boston, Massahusetts. Corresponding author: Zaldy S. Tan, ztan@hms.harvard.edu. Reeived 14 February 2011 and aepted 16 May DOI: /d This artile ontains Supplementary Data online at /d /-/DC by the Amerian Diabetes Assoiation. Readers may use this artile as long as the work is properly ited, the use is eduational and not for profit, and the work is not altered. See lienses/by-n-nd/3.0/ for details. A lzheimer s disease (AD) afflits as many as 50% of people aged.85 years and is assoiated with signifiant health are and soietal osts. With the rapid aging of the U.S. population, it is expeted that, by the year 2050, the prevalene of AD will inrease from the urrently estimated 5 million to.11 million afflited persons aged.65 years, unless effetive prevention or treatment is found (1). Beause late-onset AD is a slowly progressive disease that affets people aged.65 years, some have argued that merely delaying its onset by several years would signifiantly derease individual risk and the population burden of disease. The Framingham study estimated that a 5-year delay in the onset of AD would be equivalent to a redution of lifetime risk by half,from14to7%(2).thus,althoughvarious disease-modifying agents are being investigated, a parallel searh for modifiable risk fators that ould delay the onset of AD would be a worthwhile endeavor. Diabetes is a potentially modifiable risk fator that has been related in several population-based studies of older individuals to the risk of inident dementia and AD (3). However, the argument that it represents a ausal fator would be strengthened if similar assoiations were demonstrable relating the entire spetrum of prediabeti and diabeti states with sublinial measures of subsequent AD risk in younger persons aged,65 years whoare,asyet,freeoflinialdisease.furthermore, examining insulin resistane (IR), hyperinsulinemia, and hyperglyemia, the three interwoven omponents of the diabeti and prediabeti states, ould help larify the relative importane of these elements in determining the risk of AD. To examine the possible assoiation of midlife diabeti and prediabeti states with ognitive and brain magneti resonane imaging (MRI) markers of 1766 DIABETES CARE, VOLUME 34, AUGUST 2011 are.diabetesjournals.org

2 subsequent dementia and AD, we related diabetes, glyohemoglobin A 1 (HbA 1 ), fasting serum insulin levels, and IR in the middle-aged, ognitively intat Framingham Offspring study population to measures of strutural and funtional brain aging. RESEARCH DESIGN AND METHODS Study population The Framingham study s original ohort has been evaluated biennially sine 1948 and sreened prospetively for inident dementia sine A sample drawn from the offspring (and spouses of the offspring) of the original partiipants (Framingham Offspring ohort) was enrolled in and has been examined eight times during the past 37 years, approximately one every 4 years. artiipants who attended offspring examination 7 (between 1998 and 2001) were invited to partiipate in brain MRI studies and a neuropsyhologi assessment. The study population omprised 2,439 individuals (1,311 women), with a mean age of years who agreed to partiipate and were also free of linial stroke, dementia, or other neurologi onditions suh as a brain tumor that ould alter MRI and ognitive performane. Brain MRI study Image aquisition. The methods followed for brain MRI have been desribed previously (4). In brief, subjets underwent neuroimaging on a Siemens Magnetom (Munih, Germany) 1-T or 1.5-T field strength mahine using a double spineho oronal imaging sequene of 4-mm ontiguous slies from nasion to oiput. Imaging data were transferred to a entral loation for proessing and analyzed by operators who were blinded to the subjet s identity, age, sex, exposure to stroke risk fators, and ognitive performane on neuropsyhologi testing. reviously reported semiautomated analyses of pixel distributions based on mathemati modeling of MRI pixel intensity histograms for erebrospinal fluid and white and gray brain matter were used to determine the optimal threshold of pixel intensity to best distinguish erebrospinal fluid from brain matter (5). All analyses were performed using QUANTA 6.2, a ustom-designed image analysis pakage, operating on an Ultra 5 workstation (Sun Mirosystems, Santa Clara, CA). Assessment of brain MRI measures. MRI measures assessed onsisted of total erebral brain volume (TCBV), hippoampal volume (HV), and white matter hyperintensity volume. Brain volume was determined by manual outlining in oronal images of the intraranial vault above the tentorium to determine the total ranial volume as a measure of head size. One the skull and other nonbrain tissues were removed from the image, mathemati modeling was performed to determine total parenhymal brain volume above the tentorium (erebral). HV was estimated using operator-defined, manually traed boundaries. Beause the medial wall of the temporal horn onsists of the hippoampus, atrophy of the hippoampus will result in enlargement of the temporal horn volume. White matter hyperintensity volume was measured aording to previously published methods (6), expressed as a proportion of the total intraranial volume, and log-transformed to normalize its distribution. We estimated the equivaleny between the mean hange in TCBV assoiated with hronologi aging and that assoiated with the presene of diabetes by dividing the regression oeffiient for diabetes by the regression oeffiient for age (7). Cognitive evaluation A omprehensive, well standardized, neuropsyhologi test battery was administered to all partiipants and has been desribed previously (8). The neuropsyhologi evaluation onsisted of a 40-min test battery that inluded tests of verbal memory and abstrat reasoning that were previously assoiated with an inreased risk of developing AD in the original ohort (9). Also inluded were tests of frontal exeutive funtion that are sensitive in deteting ognitive impairment in personswithdiabetes(10).theognitive domains that we studied were verbal memory (Wehsler Memory Sale Logial Memory), visual memory (Wehsler Memory Sale Visual Reprodution), and exeutive funtion (Trail Making Tests A & B). The MRI and neuropsyhologi testing were performed on the same day for most partiipants and, in all ases, by evaluators who were blind to the diabetes, HbA 1,fasting insulin, and IR data. Diabeti and prediabeti states Fasting gluose, HbA 1,andfastinginsulin levels were estimated from blood samples drawn at the Offspring examination 7 after partiipants had fasted overnight for at least 8 h. Diabetes was determined by use of insulin or other diabetes mediation or a fasting gluose onentration $126 mg/dl. Fasting gluose onentrations were measured in fresh speimens with a hexokinase reagent kit (A-gent Gluose Test; Abbott Laboratories, In., South asadena, CA); the intra-assay oeffiient of variation (CV) was,3%. HbA 1 was measured using highperformane liquid hromatography (HLC) assays standardized to Diabetes Control and Compliations Trial values by the National Glyohemoglobin Standardization rogram (11). The HbA 1 assays have intra- and interassay CVs,3%. Assay drift in the HLC method used in Framingham Offspring Study is prevented by the use of long-term stored referene samples. lasma insulin onentrations were measured using the Coat-A-Count 125 I labeled radioimmunoassay (Diagnosti roduts, Los Angeles, CA); this assay has a ross-reativity with proinsulin at the midurve of 40%; the intra- and interassay CVs were 5 to 10%. IR was estimated using a standardized measure of insulin sensitivity: the homeostasis model assessment of IR (HOMA-IR). The HOMA-IR (mmol/l 3 mu/ml) formula is defined as fasting insulin (mu/ml) times fasting gluose (mmol/l)/22.5. Statistial analyses We related presene or absene of diabetes and levels of HbA 1, fasting insulin, and HOMA-IR to the MRI and ognitive outomes listed in RESEARCH DESIGN AND METHODS. Data for partiipants reeiving insulin treatment were exluded in the analyses involving insulin levels. We onstruted linear regression models adjusted for ovariates previously shown to affet brain volume and ognitive funtion in the Framingham ohort inluding: Tan and Assoiates ModelA:age,sex,eduation(forognitive measures) only; Model B: the above with inlusion of nondiabetes ardiovasular risk fators at examination 7: systoli blood pressure, smoking, prevalent ardiovasular disease; Model C: additional adjustment for fators previously assoiated with risk of dementia in the Framingham original ohort, namely, apolipoprotein E (apoe)- 4 genotype, and serum homoysteine levels, C-reative protein (CR), and interleukin-6 (IL-6) at examination 7. We also adjusted for the time interval between examination 7 and MRI or ognitive testing in all analyses. are.diabetesjournals.org DIABETES CARE, VOLUME 34, AUGUST

3 Metaboli dysregulation and brain volume In seondary analyses, we exluded subjets with linial diabetes and looked at the effet of the duration of diabetes on the relationship between diabetes and MRI measures by stratifying the subjets into three ategories: 1) nondiabeti as determined at Offspring examination 7 and at the earlier examination 5 ( ) using the same riteria desribed earlier (referent); 2) nondiabeti at examination 5 and diabeti at examination 7; 3) diabetiatexaminations 5 and 7. RESULTS The harateristis of the study population at examination 7 ( ) are presented in Table 1. We observed an inverse assoiation between all indies (diabetes, HbA 1, HOMA-IR, fasting insulin level) of metaboli dysfuntion evaluated at examination 7 and TCBV in all models (Table 2). Adjustment for ovariates (models B and C; Table 2) did not appreiably alter these assoiations. The observed differene in TCBV of 1.24% between partiipants with and without diabetes was equivalent to the effet of approximately 6 years of hronologi aging. Of note, the assoiation of IR and hyperinsulinemia with TCBV remained signifiant when the analysis was restrited to subjets who had not yet developed linial diabetes (Table 3). In ontrast, none of the metaboli indies were assoiated with HV. Considering the ognitive measures, we found that examination 7 diabetes and HbA 1, HOMA-IR and fasting insulin were eah related to poorer exeutive funtion. This inverse relationship between exeutive funtion and HbA 1, HOMA-IR, and fasting insulin persisted even after adjustment for ovariates (Table2)andtheexlusionofpartiipants with linial diabetes from the analysis (Table 3). HOMA-IR and fasting insulin, but not linial diabetes or HbA 1,were inversely related to visuospatial memory (Table 2). These assoiations remained signifiant after adjustment for ovariates (models B and C; Table 2). A surprising finding was an apparent assoiation between diabetes and better performane in verbal memory tasks, although this effet was attenuated after adjustment for all ovariates. There was an interation with insulin levels, so that this apparent benefiial effet was only seen in subjets who also had elevated plasma insulin levels and was not seen in the subsample of partiipants who were not reeiving insulin. Stratifying partiipants aording to their diabetes status at examination yles 5 and 7 revealed that the ross-setional assoiation between diabetes and TCBV was present only in those partiipants who had diabetes at both examination yles (diabetes duration $4 years;, 0.001) and not in those who developed diabetes only at examination 7 ( = 0.113). No suh differential patterns aording to length of time with linial diabetes were observed for the other indies of metaboli dysfuntion and measures of brain aging (Supplementary Table 1A). Table 1 Charateristis of subjets at examination yle 7 ( ) Charateristi Women Men n 1,311 1,128 Age (years) High-shool degree Current igarette smoking Systoli blood pressure ApoE lasma homoysteine (mmol/l) CR (mg/l) IL-6 (pg/ml) Diabetes Fasting gluose (mg/dl) HbA 1 (%) HOMA-IR (mmol/l 3 mu/ml) Fasting insulin (mu/ml) Time interval (years) Examination 7 to MRI Examination 7 to ognitive test Continuous data are presented as mean 6 SD; ategori data as perentages. CONCLUSIONS In the middle-aged ommunity sample of stroke- and dementiafree Framingham Offspring partiipants, we observed that linial diabetes and various metaboli indies assoiated with diabeti and prediabeti states were assoiated with the sublinial hanges of smaller brain volumes and poorer ognitive performane, espeially on tests of exeutive funtion and visual memory. These findings were observed even among partiipants who did not have linial diabetes, and the most onsistent assoiation was with IR, whih is important in the evolution of linial type 2 diabetes. The relationship between diabetes and ognition was reported.85 years ago, when Miles and Root (12) observed that patients with diabetes did not perform as well as ontrol subjets in tests of memory,mentalarithmeti,andpsyhomotor effiieny. Multiple studies sine then have shown an adverse effet of baseline diabetes status on onomitant ognitive funtion and ognitive deline on follow-up. Diabetes has been assoiated with ognitive hanges that affet learning and memory, mental speed, and mental flexibility (13), and population-based studies have also related diabetes to the risk of inident dementia and AD (3). The Memory in Diabetes (MIND) substudy of the Ation to Control Cardiovasular Risk in Diabetes (ACCORD) trial showed an inverse relationship between glyohemoglobin levels and performane on ognitive tests; whereas, fasting plasma gluose, a measure with greater day-to-day variability, was not assoiated with test performane (14). The ognitive impairment assoiated with diabetes may begin even before the appearane of linial disease; ompared with women with normal gluose, women with impaired fasting gluose levels had worse baseline ognitive sores and an almost twofold risk of developing ognitive impairment over a 4-year period (15). The pathophysiologi mehanisms underlying the purported relationship between diabetes, prediabetes, and dementia, thus far, remains unlear but ould involve diret effets on AD neuropathology or indiretly via diabeti vasulopathy, leading to erebrovasular brain injury. Hyperglyemia an be harmful by promoting oxidative stress, the formation of toxi advaned glyation end produts, and indution for reeptors for advaned glyation end produts. A diret effet of insulin on ognition is supported by observations that insulin readily rosses the 1768 DIABETES CARE, VOLUME 34, AUGUST 2011 are.diabetesjournals.org

4 Tan and Assoiates Table 2 Assoiation between metaboli dysregulation measures and markers of brain aging Variable Model HOMA-IR (mmol/l 3 mu/ml) Fasting insulin (mu/ml) HbA 1 (%) Diabetes TCBV A < < < <0.001 B < < < <0.001 C <0.001 HV A B C Verbal memory A B C Visual memory A B C Exeutive funtion A < < B < < C < < Model A: Adjusted for age, sex, eduation. Model B: Adjusted for age, sex, eduation, systoli blood pressure, smoking, history of ardiovasular disease. Model C: Adjusted for age, sex, eduation, systoli blood pressure, smoking, history of ardiovasular disease, apoe- 4 genotype, serum homoysteine levels, CR, IL-6. Statistially signifiant relationships are in boldfae. blood-brain barrier and the high onentration of insulin reeptors on the hippoampus and medial temporal ortex (16), areas of the brain that are primarily involved in memory and affeted by AD neuropathology. At exessively high or low levels, insulin has been shown in vitro to downregulate holine aetyltransferase (17), the enzyme that atalyzes the prodution of the neurotransmitter aetylholine, whih is defiient in AD. Furthermore, insulin has been impliated in t phosphorylation and amyloid deposition, the pathophysiologi mehanisms for AD (18). Diabetes is an established risk fator for stroke and other vasular disorders, leading to an alternate hypothesis that the link between diabetes and dementia is indiret, mediated by vasular pathology (19). In the Rotterdam Study, however, diabetes was assoiated with MRI markers of AD risk, inluding smaller hippoampus and amygdala volumes, even after aounting for vasular pathology (20). We found that, in this late adult population with a mean age of 62 years, linial diabetes and eah of the metaboli dysfuntion markers of IR, hyperinsulinemia, and hyperglyemia (elevated HbA 1 ) were assoiated with signs of aelerated brain aging, as measured by MRI TCBV, and by poorer performane on tests of exeutive funtion. The assoiation with IR and hyperinsulinemia, whih are early markers of a ompensated prediabeti state, were also observed in a subsample without linial diabetes. In addition, we found that there appear to be different patterns of assoiation between markers of a hyperglyemi stateversusmeasuresofirwheneahis related to ognitive markers of aging. Measures of IR (HOMA-IR and fasting insulin levels) were inversely assoiated with visual memory and exeutive funtion, whereas glyemi indies (diabetes and HbA 1 ) were inversely assoiated only with performane on exeutive funtion. We also found a marginally signifiant diret assoiation between diabetes and verbal memory, whih disappeared after adjusting for all ovariates. This finding is ontrary to previously published studies and may be a hane artifat given our ohort s younger average age ompared with previous studies. Beause it was restrited to persons on insulin supplementation, it ould reflet a benefiial effet of exogenous insulin on memory (21). Our data strengthen earlier findings relating diabetes status to ognitive funtion, even in stroke- and dementiafree ommunity-dwelling middle-aged men and women. Taken together, these findings suggest that the insulin resistant states seen in prediabetes and diabetes, as well as hyperglyemia, aelerate brain strutural and ognitive aging, albeit in slightly different patterns, with the most robust assoiations being with IR. In ontrast to investigations into the assoiation between glyemia and ognition, fewer studies have explored the possible links between insulin levels and Table 3 Assoiation between metaboli dysregulation measures and markers of brain aging after exlusion of partiipants with linial diabetes* Variable HOMA-IR (mmol/l 3 mu/ml) Fasting insulin (mu/ml) HbA 1 (%) TCBV , , HV Verbal memory Visual memory Exeutive funtion Values in boldfae type are signifiant. *Adjusted for age, sex, and eduation (for ognitive measures). are.diabetesjournals.org DIABETES CARE, VOLUME 34, AUGUST

5 Metaboli dysregulation and brain volume IR, and brain struture and ognitive performane. Although hyperinsulinemia has been diretly linked (22) to AD risk, there is also aumulating evidene linking insulin levels and ognitive performane in individuals without dementia. Hyperinsulinemia has been assoiated with lower sores on the Mini-Mental State Examination in individuals without dementia (23). Furthermore, IR, as measured by the HOMA-IR, has likewise been assoiated with poorer ognition and, more reently, with diffusely dereased ortial gluose uptake on fluorodeoxygluose-positron emission tomography sans (24,25). Our findings of inverse relationships between fasting insulin levels, HOMA-IR, and brain volume and ognitive performane even after ontrolling forvasularriskfators appear to support these findings. One limitation of our study is that we only examined a ross-setional assoiation but did not examine the assoiation of these measures with hange. Another limitation is the primarily white ethniity of the Framingham study sample; hene, these assoiations need to be examined among ommunity-dwelling individuals of other ethniities. Our results do support ongoing studies to examine whether early detetion and management of diabetes and metaboli dysfuntion, partiularly IR, would be able to delay the linial onset of ognitive disorders. Diabeti and prediabeti states haraterized by IR, hyperinsulinemia, and hyperglyemia, when present in late middle age, are related to dereased brain volume and lower ognitive performane on exeutive funtion and memory tasks. These results extend the body of evidene linking metaboli dysfuntion to the risk of dementia and AD in late life. These results suggest that linial trials attempting to delay ognitive and strutural brain loss by ontrolling metaboli dysfuntion, even in individuals free of linial diabetes and as early as the 7th deade, might be warranted. Aknowledgments This work was supported by the Framingham Heart Study s National Heart, Lung, and Blood Institute ontrat (N01- HC-25195) and by grants from the National Institutes of Health, National Institute of Neurologi Disorders and Stroke (R01-NS-17950) and from the National Institute on Aging (R01-AG-16495; AG-08122; AG ; AG ). S.D. reeived an award from the Bettenourt-Shueller Foundation. No potential onflits of interest relevant to this artile were reported. Z.S.T. researhed the data, ontributed to the disussion, and wrote the manusript. A.S.B. researhed the data, ontributed to the disussion, and reviewed and edited the manusript. C.S.F. and R.A. ontributed to the disussion and reviewed and edited the manusript. J.J.H. researhed the data and reviewed and edited the manusript. S.D. ontributed to the disussion and reviewed and edited the manusript. C.D. researhed the data and reviewed and edited the manusript. 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