CHAPTER 24 AND COGNITIVE IMPAIRMENT José A. Luchsinger, MD, MPH, Christopher Ryan, PhD, and Lenore J. Launer, PhD

Dr. José A. Luchsinger is Associate Professor of Medicine and Epidemiology, Columbia University Medical Center, New York, NY. Dr. Christopher Ryan is Director, Human Research Protection Program, University of California San Francisco, San Francisco, CA. Dr. Lenore J. Launer is Senior Investigator and Chief, Neuroepidemiology Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Bethesda, MD.

SUMMARY

Cognitive impairment, ranging from mild cognitive impairment to dementia, is increasingly recognized as a potential complication of diabetes. The increase in the prevalence of diabetes along with the aging of the population may result in a large increase in the prevalence of cognitive impairment in persons with diabetes. Approximately one-third of the United States adult population has or diabetes. However, about one-half of persons age ≥60 years, who are most at risk for cognitive impairment, have prediabetes or diabetes. The association of diabetes and cognitive impairment may reflect a direct effect on the of or the effects of the diabetes-associated comorbidities, such as , dyslipidemia, or hyperinsulinemia. There is evidence for an effect of diabetes-related processes on both neurodegenerative and vascular processes, thus contributing to both Alzheimer’s-like cognitive impairment, i.e., amnestic, and cerebrovascular-type cognitive impairment characterized by impairment in executive cognitive function.

This chapter reviews epidemiologic studies of the association between diabetes and cognitive impairment in large clinical or community- based studies, emphasizing studies in the United States. is, in general, related to modest decrements in cognitive abilities, primarily in executive-frontal abilities. seems to be more strongly related to vascular and non-amnestic forms of cognitive impairment, including non-amnestic mild cognitive impairment and vascular dementia, but it also seems to have a less strong association with amnestic forms of cognitive impairment, including amnestic mild cognitive impairment and Alzheimer’s dementia.

The relation of diabetes to cognitive impairment has therapeutic implications. There is conflicting evidence from clinical trials of diabetes interventions examining the effects of better control on and the brain. Lifestyle interventions among persons with diabetes and prediabetes do not seem to be related to better cognitive outcomes in the long term.

Despite many studies documenting the association between diabetes and cognitive impairment, the causal nature and the mechanisms of this association have not been fully established and require further study.

INTRODUCTION

This chapter describes important DESCRIPTION OF COGNITIVE Performance in Cognitive Tests concepts in cognitive impairment and IMPAIRMENT The most frequently studied cognitive epidemiologic data on cognitive impair- To study cognitive impairment, persons domains broadly defined are ment in the general U.S. population. with and without diabetes are compared in and executive-frontal abilities. Memory Then, the relationship between diabetes performance of cognitive tests and by the can be defined as the ability to recall an and cognitive impairment is explored, presence or absence of cognitive dis orders, experience after it has ended (1). Memory including potential mechanisms and such as mild cognitive impairment (MCI) is tested by repetition of words usually epidemiologic data linking the two and dementia. A brief description of these delivered verbally as lists of several words conditions, as well as implications for types of cognitive impairment follows. or as a part of tests of global cognition, treatment and prevention. The review Importantly, in this chapter, Alzheimer’s such as the 5-minute recall of three of the epidemiologic data from diabetic (AD) is referred to as one items in the Mini Mental Status Exam (2). cohorts emphasizes large longitudinal pathologic process underlying cognitive Memory problems are probably the most studies in the United States and Canada impairment, characterized by the presence frequent cognitive complaints that bring and clinical trials when available. Both of amyloid plaques and neurofibrillary patients to medical attention. Several key type 1 diabetes and type 2 diabetes are tangles on brain autopsy, and not the processes are involved in the long-term covered in this chapter. manifestation of cognitive impairment, maintenance of . Consolidation, a frequent source of confusion. Dementia, primarily located in the hippocampal the most severe clinical manifestation of formation, enables the acquisition of new AD, is referred to as AD dementia. memories (1). Consolidation is the first

Received in final form February 12, 2016. 24–1 DIABETES IN AMERICA, 3rd Edition and most prominently affected process in considered large. Some sections of this This relative lack of research is particularly AD dementia and its antecedent, amnestic chapter make reference to Cohen’s d in relevant to persons with diabetes, who MCI. Another key memory process is the interpretation of effect sizes. likely have cerebrovascular disease and, retrieval (1), which is most affected thus, are at high risk of cognitive impair- by lesions disturbing the frontal lobe-​ Mild Cognitive Impairment ment involving executive-frontal functions. subcortical circuits in the brain. Retrieval MCI is a diagnostic category used to deficits manifest as difficulty in recalling capture the transitional state between Dementia words or objects that can be aided by normal cognitive function and dementia Dementia is a syndrome characterized by giving multiple choice options or cues (6,7) and has become a target for inter- impairment of memory and other cogni- (recognition). ventions (8). The feature that differentiates tive abilities, as well as behavior disorder MCI from dementia is functional impair- severe enough to impair the ability to live Executive-frontal abilities include those ment: individuals with MCI still have the independently (11). Dementia is the most skills that are used to plan and execute ability to function in daily activities (7), extreme form of cognitive impairment and complex tasks and comprise different while persons with dementia do not. In the one most often identified in research processes, such as attention, working MCI, general cognitive performance is well and clinical practice due to its clinical memory, and impulse control. Executive- preserved, but performance in one cogni- significance. The most common cause of frontal abilities are most often affected by tive domain falls below expectations for late-onset dementia is AD (12), comprising lesions that disrupt the frontal subcortical age and education. Typically, it is defined between 60% and 80% of cases. Vascular networks (3), the same network that following cutpoints of “pass/fail” results dementia is the second most common supports memory retrieval. A common on neuropsychological tests (e.g., 1.5 cause, comprising about 10% of cases, but type of lesion that can affect frontal standard deviations of established norms). approximately 50% of cases of dementia subcortical networks in diabetes is cere- This threshold is arbitrary, and the field have a vascular component (12). Memory brovascular disease. Commonly used of cognitive disorders has become inter- may be affected in vascular dementia, but tests of executive-frontal abilities include ested in even milder forms of cognitive the main cognitive domains affected are digits forward and backward (a test in impairment (e.g., using a threshold of generally related to executive-frontal abil- which persons are asked to repeat a 1.0 standard deviations rather than 1.5), ities. An important subgroup of dementia number series forward and backward), which some have termed pre-MCI (9). cases, the size of which likely differs the attention items of the Mini Mental across populations, has mixed pathology, Status Exam (2), and the Digit Symbol MCI can be classified as amnestic and having both neurodegenerative lesions Substitution Test (DSST) of the Wechsler non-amnestic MCI. Amnestic MCI involves typical of AD and cerebrovascular disease, Adult Intelligence Scale (4). memory impairment, while non-amnestic which is “typical” of vascular dementia MCI involves predominantly non-memory (13). This mixed dementia is particularly An important consideration about the domains, such as frontal-executive abilities. important when discussing cognitive evaluation of performance on cognitive Amnestic MCI is believed to be an early impairment in diabetes, because diabetes tests as outcomes is the judgment of the manifestation of AD and an antecedent is well known to be a for cere- clinical significance of differences found of AD dementia, while non-amnestic MCI, brovascular disease (14), but whether it between groups, for example, between such as executive MCI, may be a form of causes neurodegenerative disease is less persons with diabetes and those without vascular cognitive impairment (VCI) (6). clear (10). Other causes of dementia, such diabetes. Some studies will report that In VCI, cognitive impairment may present as frontotemporal dementia and Lewy persons with diabetes perform less well slowly and incrementally as subclinical body disease, are less common (15), are in a test than persons without diabetes cerebrovascular disease worsens (seen not known to be related to diabetes, and and provide a difference size or the score as white matter hyperintensities [WMH] are thus not discussed in this chapter. in performance in both groups. It can be on brain imaging, called mini-strokes concluded from such data that persons by clinicians, and “silent infarcts”), or it EPIDEMIOLOGY AND BURDEN with diabetes will perform less well may suddenly appear after an infarct. In OF COGNITIVE IMPAIRMENT IN than persons without diabetes, but the general, VCI affects executive-frontal abil- THE GENERAL U.S. POPULATION clinical importance of such a difference ities and memory retrieval and, similar to Frequency is un­certain. One way to overcome this amnestic MCI, may or may not progress to Major epidemiologic studies have shown problem is by providing standardized the syndrome of dementia. Some experts that dementia prevalence increases loga- differences. One common metric used believe that the cognition field has paid rithmically after age 70 years (16) and is Cohen’s d (5), which is calculated more attention to cognitive impairment may reach 50% in persons age ≥85 years as the difference between the means due to AD to the detriment of the iden- (17). According to the 2014 Alzheimer’s divided by the pooled standard deviation. tification of the other forms of cognitive Disease facts and figures report from A Cohen’s d of 0.2 is considered small, impairment described here, particularly the Alzheimer’s Association (12), 11% of 0.5 is considered medium, and 0.8 is those related to executive abilities (10). people age ≥65 years and one-third of

24–2 Diabetes and Cognitive Impairment people age ≥85 years have late-onset AD It is important to put the epidemiology prevention (30) have received the most dementia. Given the longer life expectancy of cognitive impairment in the context attention in studies of causes, prevention, of the population, cases of AD dementia of the epidemiology of diabetes in the and treatment of AD. in persons age ≥65 years are expected to United States. Over 100 million U.S. increase by 40% from current numbers adults have diabetes or prediabetes: In 2010, an expert panel from the by 2025 (12). Estimates from the 2010 25 million have diabetes and 79 million National Institutes of Health concluded Census revealed that in 2010, there were have prediabetes (22), comprising that there was insufficient evidence to 4.7 million cases of AD dementia, of one-third of the U.S. population. This recommend treatment or prevention for whom 0.7 million were age 65–74 years, high prevalence is accounted for in AD dementia (31). The genetic causes 2.3 million were 75–84 years, and 1.8 large part by the age group most at risk of early-onset, familial AD dementia are million were ≥85 years (18). Based on for cognitive impairment, persons age known (32), but this form represents a these estimates, the projected number of ≥60 years in whom the prevalence of minority of cases and is not the focus of AD dementia cases in 2050 will be 13.8 pre diabetes and diabetes is >50% (>60% this chapter. APOE-ε4, encoding a form million, with 7.0 million age ≥85 years. in minorities) (22,23). A large proportion of apolipoprotein E, is the only robust AD dementia is the sixth leading cause of of this prevalence is accounted for by genetic susceptibility risk factor for late- in the United States and the fifth non-Hispanic blacks and Hispanics onset AD dementia, occurring in up to leading cause for those age ≥65 years (22,24,25), who have about twice the 50% of cases. However, it has not proved (15). As previously mentioned, vascular prevalence of diabetes compared to useful for diagnosis, prevention, or treat- dementia is the second most common non-Hispanic whites (22,24). ment (33,34,35). In addition, APOE-ε4 cause, comprising about 10% of cases, has lower predictive value in non-His- but approximately 50% of all cases of An interesting aspect of dementia is that panic blacks and Hispanics compared dementia have a vascular component (12). it has ethnic differences similar to those to non-Hispanic whites (27,33). Among found in type 2 diabetes. In a study from nongenetic risk factors, older age, lower The prevalence of amnestic MCI varies Northern Manhattan in New York City, education, and diabetes (36) are the most from 3% to 20% depending on the criteria Hispanics and non-Hispanic blacks had robust. Studies of hypertension in relation applied (19) and the population studied. approximately double the prevalence to dementia have shown that mid-life Estimates increase from about 1% in of dementia compared to non-Hispanic exposure to risk factors may be a better persons age 60 years to 25% at age 85 whites (26,27). In the same cohort from indicator of future risk for dementia than years (20). The Aging, Demographics, and Northern Manhattan, it was estimated measures obtained close to the time that Memory Study estimated the prevalence that the higher prevalence of diabetes in cognitive impairment is detected (37,38). of cognitive impairment without dementia, minorities could account for some of the Other factors, such as smoking, dyslip- similar to MCI, in a representative sample ethnic disparities in cognitive impairment, idemia, diet, and physical activity, have of 856 persons in the United States (21). including MCI and dementia, among been studied, but results are inconsistent Twenty-two percent of persons age ≥71 persons age ≥65 years (28). (39). Risk factors for VCI (40) are mainly years met the study criteria for cognitive those associated with cerebrovascular impairment without dementia. Among Causes, Risk Factors, Prevention, and disease, including diabetes and other those, 8% died and 12% progressed to Treatment of Cognitive Impairment vascular risk factors, such as hyperten- dementia on an annual basis. Persons The pathologic hallmark of AD is the sion and dyslipidemia (41). with amnestic MCI may progress to AD presence of amyloid plaques and neuro- dementia at the rate of nearly 10%–15% fibrillary tangles identified in that per year (6) compared to 1%–2% in elderly have come to autopsy (29). To date, persons with normal cognition (7). the accumulation of amyloid and its

POTENTIAL MECHANISMS LINKING DIABETES AND COGNITIVE IMPAIRMENT

Diabetes and its related conditions, potential mechanisms linking diabetes The mechanisms for the association with adiposity and hyperinsulinemia, and with cognitive impairment are classified as AD dementia are not clear. However, the their clustering with other vascular cerebrovascular and non-cerebrovascular. presence of infarcts in persons with AD risk factors, such as hypertension and neuropathology may result in an increase dyslipidemia (42), are known to increase CEREBROVASCULAR SUBSTRATES in brain injury and increase the likelihood of the risk for cerebrovascular disease Infarcts, ascertained by clinical history reaching a clinical dementia endpoint in the (14,41,43,44,45,46). In addition, as strokes causing neurologic deficits presence of such neuropathology (50,51). or diabetes-related byproducts may affect (48) or identified as focal lesions on brain the amyloid cascade that is thought imaging (49), are related to a higher risk to be responsible for AD (47). Thus, of AD dementia and vascular dementia.

24–3 DIABETES IN AMERICA, 3rd Edition

FIGURE 24.1. Relation of Glycemia and to Risk of Alzheimer’s Disease Neuropathology, the Hisayama Study, 1998–2003

Model 1 Model 2 A B C 6 6 * 6 * 5 5 5 4 4 4 † * 3 * 3 * 3 2 2 2 Odds ratio Odds ratio Odds ratio 1 1 1 (n) (45) (46) (44) (n) (37) (52) (45) (n) (45) (46) (43) 5.9 5.9 to .6 .6 4 4 to 6 6 .97 .97 to 1.77 1.77 2-hour Post-load Plasma Glucose (mmol/L) Fasting Insulin (μU/mL) HOMA-IR

Odds ratios for each tertile of (A) glucose, (B) insulin, and (C) HOMA-IR versus the lowest tertile for the presence of neuritic plaques. Model 1: adjusted for age and sex. Model 2: adjusted for age, sex, systolic pressure, total cholesterol, body mass index, current smoking, regular , and cerebrovascular disease. Conversions for glucose and insulin values are provided in Diabetes in America Appendix 1 Conversions. HOMA-IR, homeostasis model assessment of insulin resistance. * p<0.05 versus the lowest tertile † p<0.10 versus the lowest tertile SOURCE: Reference 87, copyright © 2010 Wolters Kluwer, reprinted with permission

White matter disease, called mini-strokes in important brain structures, including their receptors (RAGE) (70,71,72), and by clinicians, is ascertained as WMH, also the and entorhinal cortex, AGEs are known to be related to the tradi- known as leukoaraiosis, on brain imaging are affected early in AD (62). Insulin and tional microvascular complications of type (40). WMH may represent microvascular amyloid are competing substrates for 2 diabetes (73,74,75,76,77,78). Increased disease in the brain or demyelination. insulin-degrading enzyme, which has been expression of RAGE is also observed in AD However, the nature of WMH is still not linked to clearance of amyloid in the brain dementia (79,80,81), and expression of well understood. WMH are thought to be (63). Insulin in the brain can increase the RAGE is enhanced in blood vessels near ischemic in origin in the same way that deposition of amyloid and Tau protein amyloid deposits in AD brains (79,82). infarcts are (52) and, thus, have been phosphorylation, which are central to the proposed as surrogate markers of cerebro- pathogenesis of AD (60). The pathways Several studies have examined the vascular disease (52). However, WMH are relating insulin in the periphery with relation between diabetes and dementia common in AD dementia, and some may amyloid clearance in the brain are multiple mechanisms, particularly surrogate be related to cerebral amyloid angiopathy and complex (64). One potential pathway markers of AD, and found conflicting (53,54,55,56), a correlate of AD, inflam- is that peripheral hyperinsulinemia down- results. These markers have included mation, or other demyelinating processes. regulates insulin uptake in the blood brain neuropathology studies, brain imaging WMH are common correlates of cognitive barrier due to saturation over physiologic studies, and studies of other biomarkers. impairment in diabetes (57), but it is levels (65). This may result in reduction Neuropathology studies from 233 partic- unclear whether these WMH are markers of insulin levels in the brain, as well as ipants in the Religious Orders Study, a of microvascular injury or if they represent downregulation of the expression of insu- study of deceased older Catholic nuns, a process related to amyloid deposition or lin-degrading enzyme (66) and reduction priests, and brothers from across the another neurodegenerative process. in its related amyloid clearance function United States (83), and from a study (63). This complex observation has been of 385 nursing home residents who NON-CEREBROVASCULAR used to support the seemingly paradoxical underwent autopsy (84) found that a MECHANISMS use of rosiglitazone, an insulin sensitizer was not related to AD Hyperinsulinemia caused by insulin resis- (67,68), and intranasal insulin (69) in the neuropathology, similar to a study in a tance is an important antecedent and treatment of AD dementia. Finnish population (85). However, a study companion of type 2 diabetes (58,59). of Japanese Americans in Hawaii found Hyperinsulinemia is a plausible risk factor Advanced glycation endproducts (AGEs) that diabetes was associated with higher for AD dementia, independent of cere- are closely linked with glycemia and prevalence of AD neuropathology (86). brovascular disease for several reasons. diabetes and have also been related to The most compelling neuropathology Insulin can cross the blood brain barrier AD. (A1c), used by study to date found, in a Japanese sample, (60), and peripheral insulin infusions in clinicians to track diabetes control, is the that increased glycemia and insulin the elderly may affect amyloid levels in most common example of an AGE. With resistance measured 10 years before cerebrospinal fluid (61), an indirect marker hyperglycemia, diabetic animal and autopsy were related to increased risk of of AD risk. In addition, insulin receptors human tissues increase both AGEs and AD neuropathology (Figure 24.1) (87). One

24–4 Diabetes and Cognitive Impairment brain imaging study in the United States FIGURE 24.2. Patterns of Brain and Amyloid Brain Accumulation by Positron found that insulin resistance was related Emission Tomography, by Diabetes Status and Cognitive Impairment, Mayo Clinic Study of to a profile of brain metabolism on brain Aging, 2006–2012 positron emission tomography (PET) that is consistent with AD (88). Similarly, 2. 2. another brain imaging study from the United States among 749 persons with a mean age of 79 years found that diabetes 1.5 1.5 was associated with a brain metabo-

lism pattern similar to AD, but not with FDG ratio 1. 1. increased amyloid brain accumulation, as ascertained with brain PET with an amyloid ligand (Figure 24.2) (89). A study .5 P = .1 .5 P = .1 from the Baltimore Longitudinal Study No DM DM No DM DM of Aging (BLSA) (90) found among 197 persons with autopsy at a mean age 3.5 3.5 of 88 years that hyperglycemia, insulin resistance, and diabetes assessed 3. 3. approximately at age 66 years were 2.5 2.5 not associated with increased brain AD

pathology. The same study had data PIB ratio 2. 2. on 53 subjects with brain amyloid PET acquired at a mean age of 79 years and 1.5 1.5 also found no evidence of a relation with 1. P = . 1. P = . brain amyloid. No DM DM No DM DM Cognitively normal MCI The conflicting results of these studies do not help resolve the question of Box plots for 18F-FDG and 11C-PiB retention ratio in Alzheimer’s disease signature regions by diabetes mellitus (DM) whether diabetes is related to brain in cognitively normal subjects and those with mild cognitive impairment (MCI). ˜ = women; š = men. amyloid accumulation. The limitations SOURCE: Reference 89, copyright © 2014 Society of Nuclear Medicine and Molecular Imaging, reprinted with permission of the neuropathology studies include survival bias and selection bias and the that found that hyperglycemia and insulin from survival and selection biases (i.e., lack of proper ascertainment of diabetes resistance were related to AD pathology persons with diabetes may have a higher status compared with the previously (87). The limitations of the few amyloid mortality risk that could result in survival mentioned Japanese study with detailed brain imaging studies include old age and bias and affect the study of dementia and data on glycemia and insulin resistance small clinic samples, which also suffer neuropathology outcomes).

TYPE 1 DIABETES AND COGNITIVE IMPAIRMENT

Historically, most research on the rela- defined in terms of performance differ- among those children and adolescents tionship between type 1 diabetes and ences between demographically similar with diabetes. Effects were largest for cognitive impairment was conducted on subjects with and without diabetes. Most measures of “crystalized intelligence”— relatively small “convenience” samples, recent studies have expressed these as factual information about the world, verbal and was restricted to children or young standardized differences (e.g., z score learning, and visual and motor integration. and middle-aged adults. Cognitive status differences; Cohen’s d) (93). With very Because a number of studies have consis- was typically measured with a battery of few exceptions (94,95), researchers have tently indicated that children with an “early neuropsychological tests that assessed not made formal ratings of clinically onset” of diabetes—usually diagnosis multiple cognitive domains, including significant impairment like dementia or before age 6 or 7 years—perform more attention/concentration, learning and MCI, largely because it is quite unusual to poorly than those with a later onset of memory, mental and motor speed, find clinical evidence of serious cognitive diabetes (97), the meta-analysis was visual perceptual skills, and reasoning impairments in this patient population. repeated, but comparing early-onset or “executive function” (91,92). Because Drawing on results from 15 studies with later-onset subjects. The magnitude the focus was on identifying mild to comprising 1,029 subjects with diabetes of the cognitive differences was found moderate decrements in cognitive func- and 751 control subjects, Gaudieri et al. to be somewhat larger in persons with tioning, dysfunction was operationally (96) found modestly poorer performance early onset of diabetes compared with

24–5 DIABETES IN AMERICA, 3rd Edition later onset, with more domains equal to FIGURE 24.3. Meta-Analysis of Cognitive Performance Among Adults With Type 1 Diabetes or greater than an effect size (Cohen’s d) of 0.15, considered a small difference as Overall cognition () p.1 compared with controls. Taken together, Intelligence these results support the view that in Crystalized intelligence (27) p.1 children and adolescents, diabetes is Fluid intelligence (1) p.1 associated with modest decrements on a Learning and memory range of cognitive skills, with these effects Woring memory (244) being greatest in those youngsters who Visual learning and immediate memory (17) were diagnosed with diabetes early in life. Verbal learning and immediate memory (24) Another meta-analysis, adding several Visual delayed memory (15) newer studies (24 studies published Verbal delayed memory (15) between 1980 and 2005), identified a Psychomotor activity and speed of information processing generally similar pattern of results (98), Psychomotor efficiency (3) p.5 with modest differences between diabetic Speed of information processing () p.5 and nondiabetic samples (Cohen’s d Motor speed (14) 0.15–0.30) evident on tests of verbal and Attention performance intelligence, as well as on Visual attention (195) p.1 measures of visuospatial ability, motor Sustained attention (217) p.1 Cognitive domains (number of patients included) speed, attention, and and writing. Divided attention (5) Selective attention () In terms of cognition in adults with type 1 Cognitive flexibility (34) p.1 diabetes, Brands et al. (99) published a Visual perception (22) p.1 meta-analysis of 33 studies published (144) between 1980 and 2004 that included -1.6 -1.4 -1.2 -1. -. -.6 -.4 -.2 .2 .4 .6 adults age >18 years and a comparison Standardized effect sizes (Cohen’s d) and 95% intervals for the cognitive domains in patients with type 1 group of subjects without diabetes. In diabetes compared with nondiabetic control subjects. Number of patients included in each domain is listed between virtually all studies, subjects were age parentheses. Nonsignificant p-values are not shown. Points to the left of 0 indicate worse cognitive performance in <50 years at the time of the cognitive persons with type 1 diabetes compared to controls without diabetes. SOURCE: Reference 99, copyright © 2005 American Diabetes Association, reprinted with permission from The assessment. As illustrated in Figure American Diabetes Association. References for individual studies are available from Reference 99. 24.3 (99), adults with type 1 diabetes performed consistently more poorly than of children and adolescents: intelligence, severe and because earlier controls on measures of overall cognition, as measured by formal IQ tests, is studies had demonstrated that severe intelligence, psychomotor efficiency, consistently lower—by about 3 to 5 hypoglycemia could adversely affect the speed of information processing, points on average (the majority of the structural and functional integrity of the cognitive flexibility, attention, and visual general population is between 85 and brain, the DCCT study group developed a perceptual skills. The largest effect 115 points of IQ)—and performance comprehensive battery of neurocognitive sizes (Cohen’s d 0.5–0.7) were found is slower—by 5%–15%—on tasks that tests that was administered at study entry on measures of crystalized intelligence, require attention and rapid responding. and repeated at years 2, 5, 7, and/or study fluid intelligence (e.g., problem-solving, end. Data from 1,441 subjects, followed reasoning), psychomotor efficiency, and The only large-scale study to compre- for an average of 6.5 years, demonstrated cognitive flexibility, which fall under the hensively assess adolescents and adults that intensive insulin therapy did not umbrella of non-amnestic cognitive with type 1 diabetes over time is the differentially disrupt functioning on any function. It is noteworthy that with the Diabetes Control and Complications Trial of the eight cognitive domains studied. exception of measures of crystalized (DCCT), conducted in 29 sites in the Despite high rates of hypoglycemia in the intelligence, the other cognitive domains United States and Canada (100). This study group, there was no relationship that were most affected by diabetes clinical trial, which compared the effects between moderately severe hypoglycemia tended to be those that required rapid of intensive insulin therapy (multiple daily and performance on any cognitive test responding or were otherwise time- injections) with conventional therapy (one (95,101). Use of an innovative clinical limited. Despite the relatively small or two daily injections), was designed to rating procedure (102) showed very low sample sizes of the studies included in test the hypothesis that intensive therapy rates of clinically significant worsening this analysis, as well as the wide range delayed or prevented the development of over time (by year 5, only 23 of 1,383 of measures used by the different microvascular and neuropathic compli- subjects showed significant cognitive researchers, these results are remarkably cations. Because intensive therapy was decline), and these effects were unrelated consistent with those reported in studies known to increase the incidence of to hypoglycemia.

24–6 Diabetes and Cognitive Impairment

The Epidemiology of Diabetes FIGURE 24.4. Effects of DCCT Treatment Group, Severe Hypoglycemia, and Glycated Interventions and Complications (EDIC) Hemoglobin on Changes in Cognition, From Entry Into DCCT to Year 12 in the EDIC Study study, a follow-up assessment of the DCCT cohort (N=1,144), studied a mean A. Original treatment assignment Intensive treatment Conventional treatment of 18 years following study entry, also .3 showed no between-group differences on any cognitive domain nor any rela- .2 tionship between recurrent episodes of .1 hypoglycemia and change in cognitive functioning over time (Figure 24.4) (103). However, poorer metabolic control, oper- -.1 ationalized as a time-weighted A1c value Change in z score -.2 of ≥8.2% (≥66 mmol/mol), was associated with consistently poorer performance over -.3 time on two cognitive domains: psycho- -.4 motor efficiency and motor speed. 1 2 3 4 5 6 7 Cognitive Domain Subsequent analyses, focusing on predictors of cognitive changes over time, B. Number of severe hypoglycemic events demonstrated that after controlling for age No episodes 1–5 episodes 5 episodes .3 and education, proliferative retinopathy, renal complications, and time-weighted .2 A1c values were each independently and .1 significantly associated with declining performance on measures of psycho- motor efficiency 104( ). This work is -.1 consistent with earlier longitudinal studies (105) that link the development of micro- Change in z score -.2 vascular complications to psychomotor -.3 slowing in adults with type 1 diabetes. -.4 1 2 3 4 5 6 7 Cognitive Domain

C. Degree of metabolic control Glycated hemoglobin 7.4 Glycated hemoglobin ≥7.4% and ≤8.8% .4 Glycated hemoglobin . p=.1 .3 .2 .1 -.1 -.2 Change in z score -.3 p.1 -.4 -.5 1 2 3 4 5 6 7 Cognitive Domain

The bars show the changes within cognitive domains between cognitive testing at baseline in DCCT and follow-up testing (a mean of 18 years after baseline) expressed as (A) changes in z scores for intensive versus conventional treatment, (B) frequency of episodes of severe hypoglycemia (coma or ), and (C) mean glycated hemoglobin values. Across the three groups, higher levels of glycated hemoglobin were associated with moderate declines in psychomotor efficiency (p<0.001) and motor speed (p=0.001), but no other cognitive domain was affected significantly. Cognitive domains are numbered as follows: 1, problem solving; 2, learning; 3, immediate memory; 4, delayed recall; 5, spatial information; 6, attention; 7, psychomotor efficiency; and 8, motor speed. Conversions for glycated hemoglobin values are provided in Diabetes in America Appendix 1 Conversions. DCCT, Diabetes Control and Complications Trial; EDIC, Epidemiology of Diabetes Interventions and Complications study. SOURCE: Reference 103, copyright © 2007 Massachusetts Medical Society, reprinted with permission

24–7 DIABETES IN AMERICA, 3rd Edition

TYPE 2 DIABETES AND COGNITIVE IMPAIRMENT

DIABETES, COGNITIVE DECLINE, Self-reported diabetes was related to DIABETES AND DEMENTIA AND MILD COGNITIVE IMPAIRMENT a twofold higher risk of developing Numerous studies conducted in a wide The difference in cognitive function MCI among 7,027 osteoporotic post- range of ethnic groups have examined the between those with and without diabetes menopausal women with a mean age relation between diabetes and dementia is relatively robust across cohort studies, of 66 years participating in a clinical (112,113). Table 24.1 shows the results of although results vary in terms of which trial of the osteoporosis representative prospective studies in the specific functions differ between the two raloxifene in 25 countries, including United States. In general, the association groups. Over 4 years, a cohort of 999 the United States (108). A multiethnic between diabetes and dementia seems to individuals age 44–89 years was followed study of 1,088 subjects age ≥65 years be strongest for vascular dementia or AD in the Rancho Bernardo Study, a popula- in New York City found that diabetes dementia with vascular comorbidity, paral- tion-based study conducted in suburban was related to a higher risk of cognitive leling the findings for studies examining southern California. Diabetes, ascertained impairment-without dementia with cognitive performance and non-dementia by glucose tolerance testing, was associ- stroke, but not of cognitive impair- cognitive impairment as outcomes. One of ated with faster decline in a verbal fluency ment-without dementia without stroke, the most compelling reports documenting test (a test of executive-frontal abilities), after adjusting for demographic vari- the association between diabetes and but not a decline in the Mini Mental ables and the presence of the APOE-ε4 dementia came from a study of 2,067 Status Exam (a test of global cognition) allele (26). A Canadian prospective subjects age ≥65 years from Washington or Trail Making Tests (another test of study in 5,574 persons age ≥65 years State with repeated measures of glycemia executive-frontal abilities) (106). The similarly found that diabetes was related (114). In this study, increased glucose Atherosclerosis Risk in Communities Study only to VCI-without dementia (109). levels were related to a higher risk of (ARIC) was a prospective epidemiologic Another study in 918 subjects age dementia both among persons with and study of 10,963 persons age 47–70 years ≥65 years in New York City found that without diabetes. For example, for an in four U.S. communities (Washington diabetes was related to a higher risk of average glucose level of 190 mg/dL (10.55 County, Maryland; Forsyth County, North both amnestic and non-amnestic MCI, mmol/L) compared with 160 mg/dL (8.88 Carolina; Jackson, Mississippi; and highlighting the importance of diabetes mmol/L), there was a 40% increased risk Minneapolis, Minnesota). ARIC showed for both AD and VCI (110). A study of of dementia (Figure 24.5) (114). Some that diabetes, ascertained by self-report or 1,640 subjects age 70–80 years from studies have also reported a greater risk fasting glucose, was a strong predictor of Olmstead County, Minnesota, reported of dementia among persons with diabetes decline in the DSST of the Wechsler Adult that longer diabetes duration and treat- and the APOE-ε4 allele compared to Intelligence scale and the word fluency ment with insulin, a surrogate marker of persons with one of these risk factors or test, both tests of executive-frontal abili- diabetes severity, were related to higher others (86,115), suggestive of -envi- ties, after 6 years of follow-up (107). MCI risk (111). ronment interaction.

TABLE 24.1. Summary of Epidemiologic Studies From North America Relating Type 2 Diabetes and Dementia

YEARS (REF.) POPULATION SAMPLE STUDY CHARACTERISTICS STATISTICS 1970–1984 (153) Historical cohort in 1,455 persons Dementia ascertained by Persons with diabetes exhibited significantly increased risk of all Rochester, Minnesota with diabetes; medical record abstraction. dementia (RR 1.66, 95% CI 1.34–2.05) and Alzheimer’s disease age ≥45 years Standardized morbidity ratios (AD) dementia (for men, RR 2.27, 95% CI 1.55–3.31; for women, calculated using expected RR 1.37, 95% CI 0.94–2.01). age- and sex-specific dementia rates.

1991–1996 (26) Multiethnic cohort from 1,262 subjects Diabetes diagnosed by self- The adjusted relative risk of AD dementia among persons with New York City recruited without report or use of diabetes diabetes compared to those without diabetes was 1.3 (95% CI between 1992 and dementia at . Dementia and 0.8–1.9). The adjusted relative risk of stroke-associated dementia 1994 baseline; mean dementia subtype diagnosed in persons with diabetes was 3.4 (95% CI 1.7–6.9). age 75.6 years by standard research criteria.

1991–1992 (109) Canadian Study of 5,574 subjects; Diabetes diagnosed by self- Diabetes at baseline was associated with incident vascular dementia Health and Aging mean age report. Dementia diagnosed (RR 2.03, 95% CI 1.15–3.57), but not with mixed AD/vascular 74±6.4 years by research criteria. dementia (RR 0.87, 95% CI 0.34–2.21), or AD dementia (RR 1.30, 95% CI 0.83–2.03), or all dementias (RR 1.26, 95% CI 0.90–1.76). 1991 and 1994 Population-based 2,574 subjects; Diabetes ascertained by Diabetes was associated with total dementia (RR 1.5, 95% CI 1.01– (86) cohort of Japanese mean age 76.9 interview and direct glucose 2.2), AD dementia (RR 1.8, 95% CI 1.1–2.9), and vascular dementia American men enrolled years testing. Dementia assessed (RR 2.3, 95% CI 1.1–5.0). Individuals with both type 2 diabetes and in the Honolulu-Asia by research criteria. the APOE-ε4 allele had a relative risk of 5.5 (95% CI 2.2–13.7) for Aging Study AD dementia compared with those with neither risk factor.

Table 24.1 continues on the next page. 24–8 Diabetes and Cognitive Impairment

TABLE 24.1. (continued)

YEARS (REF.) POPULATION SAMPLE STUDY CHARACTERISTICS STATISTICS 1994–2003 (154) Religious Orders Study 824 nuns, Diabetes ascertained by self- Diabetes was related to higher risk of AD dementia (HR 1.65, 95% across the United priests, and report or use of medications. CI 1.10–2.47). States brothers; mean AD ascertained by research age 75 years criteria. 1964–1973 and Participants of a 8,845 subjects Diabetes ascertained when Diabetes was related to a higher risk of dementia (HR 1.46, 95% CI 1994–2003 (155) health maintenance participants were between 1.19–1.79). organization in ages 40 and 44 years. Northern California Dementia ascertained when participants were between ages 70 and 74 years. Both diabetes and dementia ascertained from medical records. 1992–2000 (115) Cardiovascular Health 2,547 subjects; Diabetes ascertained by Diabetes was only related to dementia (HR 1.44, 95% CI 1.03–2.01), Study mean age 74.67 fasting blood glucose AD dementia (HR 1.62, 95% CI 0.98–2.67), and mixed AD (HR 1.75, years or clinical history. AD 95% CI 1.00–3.04), but not vascular dementia (HR 0.80, 95% CI ascertained by research 0.30–2.09). Compared with those who had neither diabetes nor criteria. APOE-ε4, those with both factors had a significantly higher risk of AD dementia (HR 4.58, 95% CI 2.18–9.65) and mixed AD (HR 3.89, 95% CI 1.46–10.40). 1999–2007 (156) Cohort from New York 1,488 subjects; Diabetes ascertained by self- Diabetes associated with a higher risk of AD dementia (HR 1.6, 95% City recruited between mean age 76.0 report. Dementia ascertained CI 1.0–2.6) and vascular dementia (HR 5.4, 95% CI 0.3–95.0). 1999 and 2001 years by research criteria. 1994–2004 (114) Cohort from the Group 2,067 subjects; Glycemia measured Among participants without diabetes, higher average glucose levels Health Cooperative in mean age 76 with glucose or glycated within 5 years before baseline were related to an increased risk of Washington State years hemoglobin (A1c). dementia (p=0.01). For a glucose level of 115 mg/dL compared with 100 mg/dL, the adjusted hazard ratio for dementia was 1.18 (95% CI 1.04–1.33). Among participants with diabetes, higher average glucose levels were also related to an increased risk of dementia (p=0.002); for a glucose level of 190 mg/dL compared with 160 mg/dL, the adjusted hazard ratio was 1.40 (95% CI 1.12–1.76). Conversions for glucose values are provided in Diabetes in America Appendix 1 Conversions. AD, Alzheimer’s disease; CI, confidence interval; HR, hazard ratio; RR, relative risk. SOURCE: References are listed within the table.

FIGURE 24.5. Risk of Incident Dementia Associated With the Average Glucose Level During the Preceding 5 Years, According to the Presence or Absence of Diabetes, Adult Changes in Thought Study, 1994–2004

A. Participants without diabetes B. Participants with diabetes 2. 2. 1. 1. 1.6 1.6 1.4 1.4

1.2 1.2

1. 1. Hazard ratio Hazard raatio . .

.6 .6 9 95 1 15 11 115 12 14 15 16 17 1 19 2 Average Glucose Level (mg/dL) Average Glucose Level (mg/dL)

Solid curves represent estimates of the hazard ratios for the risk of incident dementia across average glucose levels relative to a reference level of 100 mg/dL for participants without diabetes (Panel A) and 160 mg/dL for participants with diabetes (Panel B). The dashed lines represent pointwise 95% confidence intervals. Conversions for glucose values are provided in Diabetes in America Appendix 1 Conversions. SOURCE: Reference 114, copyright © 2013 Massachusetts Medical Society, reprinted with permission

24–9 DIABETES IN AMERICA, 3rd Edition

Caveats in the Epidemiologic TABLE 24.2. Prevalence of Dementia in Nursing Home Residents, by Diabetes Status, Age, Study of Diabetes and Dementia Sex, and Race/Ethnicity, U.S., 2004 The study of diabetes and dementia PERCENT (STANDARD ERROR) in older age is affected by competing CHARACTERISTICS Diabetes No Diabetes risks of morbidity and mortality, which may limit the participation of persons Overall 13.8 (0.73) 21.7 (0.62) with diabetes at baseline or follow-up Age (years) <20 2 2 studies. In other words, since diabetes 20–44 2 2 is an important cause of morbidity and 45–54 2 5.2 (1.56) mortality, persons with diabetes may not 55–64 3.6 (1.21)1 10.2 (1.61) live long enough or be healthy enough 65–74 9.3 (1.46) 16.0 (1.40) 75–84 15.0 (1.29) 25.7 (1.03) to participate in prospective studies 85–94 19.5 (1.55) 24.8 (0.90) examining the association between ≥95 14.4 (3.89) 19.3 (1.55) diabetes and cognitive impairment, Sex which usually involve populations age Male 11.8 (1.17) 17.4 (1.00) ≥65 years. This issue is illustrated by Female 14.7 (0.88) 23.4 (0.69) a new analysis of the National Nursing Race/ethnicity Non-Hispanic white 15.1 (0.89) 22.6 (0.68) Home Survey 2004 conducted for Non-Hispanic black 10.5 (1.50) 17.6 (1.49) Diabetes in America, 3rd edition. This Hispanic 7.5 (2.23) 18.0 (2.90) analysis, based on International Diabetes is based on ICD-9 codes 250, 357.2, 362.0, 366.41, 648.0, and 775.1. Dementia is based on ICD-9 codes Classification of , Ninth 290, 294.1, 294.2, and 331. ICD-9, International Classification of Diseases, Ninth Revision. 1 Relative standard error >30%–40% Revision (ICD-9), medical record coding 2 Estimate is too unreliable to present; ≤1 case or relative standard error >50%. of dementia, showed the prevalence SOURCE: National Nursing Home Survey 2004 of dementia was lower in persons with diabetes (13.8%) compared to persons ethnicity groups (Table 24.2) and among conflicting results of studies examining without diabetes (21.7%) (Table 24.2). dementia cases residing inside or outside the association of diabetes and markers This difference was consistent in all age of a dementia care unit (data not shown). of AD pathology on autopsy and brain groups, both sexes, and across race/ This type of bias could also explain the imaging mentioned previously.

THERAPEUTIC AND PREVENTION IMPLICATIONS

The association between diabetes and at high risk for cardiovascular events in 77 The primary outcomes analysis of the cognitive impairment has three main sites in the United States and Canada. All MIND substudy focused on the glycemia practical implications: first, diabetes participants were randomized to receive trial and whether the intensive therapeutic treatment may alter the trajectory to either the intensive glycemic control stra- strategy compared to the standard cognitive impairment; second, interven- tegy (target A1c <6.0% [<42 mmol/mol]) or strategy reduced the risk of cognitive tions that prevent diabetes could prevent a standard glycemic control strategy (A1c decline, measured with three tests cognitive impairment; and third, specific 7.0%–7.9% [53–63 mmol/mol]), with the covering memory and executive function, diabetes medications could be used in hypothesis that the more intensive thera- in the subset of MIND participants (mean the treatment and prevention of cognitive peutic strategy would reduce the rate of age 62.5 years) (116). This analysis also impairment. cardiovascular events more than the stan- assessed total brain volume, the primary dard strategy. The trial also had embedded brain structure outcome, on a subset of DIABETES TREATMENT AND in it a trial (n=5,518), which tested MIND participants who underwent brain COGNITIVE IMPAIRMENT whether within the context of good magnetic resonance imaging. No differ- The Action to Control Cardiovascular glycemic and lipid control (target low-den- ences were found between the treatment Risk in Diabetes-Memory in Diabetes sity lipoprotein [LDL] cholesterol level groups for the cognitive outcomes, but (ACCORD-MIND) study (n=2,790) was <100 mg/dL [<2.59 mmol/L]) participants participants in the intensive treatment arm designed to examine the difference receiving a fibrate had fewer cardiovascular showed larger (better) total brain volumes between therapeutic strategies in the events than those receiving placebo. Also (TBV). At 40 months, the TBV declined rate of cognitive decline and related embedded was a blood pressure trial that in all participants, but the decline was structural brain changes (116). MIND was compared cardiovascular events between 0.41% per year in the intensive treatment embedded in the 2 by 2 factorial ACCORD a therapeutic strategy that followed stan- arm compared with 0.57% per year in the therapeutic strategy trial that randomized dard guidelines (systolic blood pressure standard treatment arm (Table 24.3) (116). 10,251 persons with longstanding type 2 <140 mmHg) and one that aimed to lower Similarly, there were no differences in the diabetes, age 55–80 years, and who were systolic blood pressure goals (<120 mmHg). cognitive outcomes in the blood pressure

24–10 Diabetes and Cognitive Impairment

TABLE 24.3. Cognitive and MRI Primary and Secondary Outcomes, by Glycemia Arm, ACCORD-MIND Study

LEAST SQUARES MEAN (95% CONFIDENCE INTERVAL) Glycemia Intervention ENDPOINT TIME POINT Intensive* Standard* DIFFERENCE IN MEANS† DSST Baseline‡ 52.55 52.55 20 months 51.51 (51.09–51.93) 50.98 (50.57–51.39) 0.53 (-0.06–1.12), p=0.0756 40 months 50.93 (50.50–51.35) 50.61 (50.19–51.03) 0.32 (-0.28–0.91), p=0.2997§ 40-month change -1.62 (-2.05– -1.20) -1.94 (-2.36– -1.52) RAVLT Baseline‡ 7.51 7.51 20 months 7.87 (7.77–7.96) 7.85 (7.76 –7.94) 0.02 (-0.11–0.15), p=0.7897 40 months 7.98 (7.88 – 8.08) 7.99 (7.90 – 8.08) -0.01 (-0.14–0.12), p=0.8929 40-month change 0.47 (0.37–0.57) 0.48 (0.39–0.57) Stroop Baseline‡ 32.0 32.0 20 months 30.87 (30.16–31.57) 31.46 (30.77–32.16) -0.60 (-1.59–0.40), p=0.2375 40 months 31.45 (30.73–32.17) 32.06 (31.34–32.77) -0.61 (-1.62–0.40), p=0.2383 40-month change -0.55 (-1.27–0.17) 0.06 (-0.66–0.77) MMSE Baseline‡ 27.39 27.39 20 months 27.26 (27.14–27.38) 27.27 (27.15–27.39) -0.01 (-0.18–0.16), p=0.9268 40 months 27.05 (26.93–27.17) 27.06 (26.93–27.18) -0.01 (-0.18–0.16), p=0.9328 40-month change -0.34 (-0.46– -0.22) -0.33 (-0.46– -0.21) MRI-TBV Baseline‡ 927.5 927.5 40 months 914.4 (912.5–916.4) 909.8 (908.0–911.6) 4.6 (2.0–7.3), p<0.0007§ 40-month change -13.0 (-15.0– -11.1) -17.7 (-19.5– -15.9) ACCORD-MIND, Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes Study; DSST, Digit Symbol Substitution Test; MMSE, Mini Mental Status Exam; MRI-TBV, magnetic resonance imaging-total brain volume; RAVLT, Rey Auditory Verbal Learning Test. * For DSST, RAVLT, and MMSE, a negative change value represents a decline in cognitive score. For the Stroop test, a positive change value represents a worsening score. For TBV, a negative change value represents a decline in volume. † Difference calculated as intensive minus standard arm means. ‡ Baseline mean is the overall mean for both groups combined as measured prerandomization. This value is used to obtain the least squares means estimates at follow-up. Models are adjusted for baseline cognitive score and the factors used to stratify randomization: second trial assignment (BP or Lipid); randomized group allocation within the blood pressure (BP) and lipid trials, respectively; clinical center network; and history of cardiovascular disease. § Test of prespecified co-primary outcome. SOURCE: Reference 116, copyright © 2011 Elsevier, reprinted with permission or lipid trials. However, one of the earlier FIGURE 24.6. Effect of a Telemedicine Intervention Versus Usual Care on Global Cognitive analyses explored the relationship between Decline, Informatics for Diabetes Education and Telemedicine Study, 2000–2007 the degree of hyperglycemia and cognitive CARE Diagnostic (mixed with clustering adjustment) status through a cross-sectional examina- Telemedicine Usual care tion of baseline glycemic control and the 1. cognitive scores obtained on the cognitive 1.6 tests at baseline. It was reported that higher A1c levels were, indeed, associated 1.4 with lower cognitive function in these 1.2 patients (117). Another set of analyses Adjusted mean found that in the MIND patients 1. was associated with accelerated cognitive . decline irrespective of which cognitive 1 2 3 4 5 domains, treatment arms, or patient Time (Years) subgroups were assessed (118). Comparison of changes in adjusted means in the Comprehensive Assessment and Referral Evaluation (CARE) Diagnostic Scale between the intervention and control from mixed models (adjusted for clustering) during a The Informatics in Diabetes Education maximum follow-up of 5 years. SOURCE: Reference 121, copyright © 2011 Springer, reprinted with permission and Telemedicine Study (IDEATel) was a randomized trial of telemedicine versus who interacted with nurse care managers all statistically significant and favoring the usual care in 2,169 elderly persons with to improve their diabetes control. Persons telemedicine intervention. Persons in the diabetes conducted in two sites in New in the IDEATel intervention group showed telemedicine intervention had less global York, a rural upstate site and an urban better diabetes control parameters cognitive decline during a maximum of downstate site (119). The telemedicine compared to usual care (120). Estimated 5 years of follow-up (Figure 24.6) (121). intervention comprised a telemedicine differences between the groups at year 5 Importantly, the glycemic control goals unit with videoconferencing, email, and were 0.29% for A1c, 3.84 mg/dL for LDL, of IDEATel followed glycemic guidelines clinical data entry capabilities for patients and 4.32 mmHg for systolic blood pressure, (target A1c <7.0%) that were less stringent

24–11 DIABETES IN AMERICA, 3rd Edition than the goals in ACCORD (A1c <6.0%), FIGURE 24.7. Path Diagram Depicting the Direct and Indirect Effects of the Telemedicine which showed increased mortality in Intervention Through Hemoglobin A1c on Cognition, Informatics for Diabetes Education and its intensive glycemic control arm (122). Telemedicine Study Although the outcome of this study was global cognitive decline, memory was the strongest correlate of global cogni- HgA1c tive function in a subset of patients with detailed neuropsychological testing. p=.379 A mediation analysis demonstrated that among diabetes control parameters, p=.2 lower glycemia measured with A1c, but not systolic blood pressure or LDL, was the main mediator for the association p=.17 Intervention between improved control and cognitive Cognition performance (Figure 24.7) (121). Other analyses from this study restricted to SAS PROC Mixed with a compound symmetry covariance structure was used in the cognition analyses with an the urban cohort in New York City found adjustment for clustering within primary care provider clusters. HgA1c was treated as a time-varying covariate in that mild memory or executive cognitive the cognition analyses. SAS PROC Mixed was used to predict HgA1c and included adjustments for clustering and heterogeneity of variances in group and residual variances and exponential terms to model the nonlinear distribution impairment (defined as cognitive perfor- of HgA1c over time. A first order auto-regressive covariance structure was used for the HgA1c analyses. Up to six mance worse than 1.0 standard deviations waves of data (baseline plus five follow-up) were included in the analyses. n=2,169. HgA1c, glycated hemoglobin. for the norms for age, sex, and education) SOURCE: Reference 121, copyright © 2011 Springer, reprinted with permission were not associated with longitudinal diabetes control (123). Depression was HYPOGLYCEMIA AND performance at the time of hypoglycemia. also not associated with diabetes control, COGNITIVE IMPAIRMENT Thus, the investigators could not rule out whether accompanied or not by mild One of the main complications of that persons who had the type of cogni- executive or memory impairment (123). diabetes treatment is hypoglycemia, tive impairment that precedes dementia However, these studies did not measure which has long been hypothesized to be a (i.e., MCI) were taking their diabetes medi- whether persons with cognitive impair- potential mechanism explaining the pres- cations inappropriately, making them ment received more assistance for their ence of cognitive impairment in diabetes. more prone to hypoglycemia. Analysis diabetes care, which could have underesti- A large longitudinal epidemiologic study of the ACCORD-MIND data showed mated the detrimental effects of cognitive in 16,667 enrollees in a managed care that persons with poor performance at impairment on diabetes control. health plan in Northern California showed baseline in the DSST, a test of frontal- that persons with diabetes with reported executive abilities, were more likely to The Action for Health in Diabetes (Look hypoglycemic events were more likely have a hypoglycemic event (127). A AHEAD) clinical trial, conducted in 21 to develop dementia (Table 24.4) (126). 5-point poorer baseline score in the DSST sites in the United States, found that a Persons with one episode of hypogly- (mean score 52.55) had a 13% increased lifestyle intervention among 978 persons cemia had approximately a 26% increased risk of a first episode of hypoglycemia with diabetes was not related to cognitive risk of dementia, while persons with three during a mean follow-up of 3.25 years. performance 8.1 years after trial enroll- or more episodes had nearly a doubling These results suggest that cognitive ment (124), despite clinically significant in risk of dementia. However, this study impairment could lead to hypoglycemia, weight loss in the intervention arm (125). did not have information on cognitive presumably because of inappropriate

TABLE 24.4. Hypoglycemia and Risk of Incident Dementia

HAZARD RATIO (95% CONFIDENCE INTERVAL)* NUMBER OF NUMBER OF Adjusted for Age (as Time Scale), Additionally Adjusted for 7-Year HYPOGLYCEMIC DEMENTIA BMI, Race/Ethnicity, Education, Additionally Adjusted for Mean A1c Level, Diabetes EPISODES† CASES Sex, and Duration of Diabetes Comorbidities‡ Treatment, and Years of Insulin Use 1 or more 250 1.68 (1.47–1.93) 1.48 (1.29–1.70) 1.44 (1.25–1.66) 1 150 1.45 (1.23–1.72) 1.29 (1.10–1.53) 1.26 (1.10–1.49) 2 57 2.15 (1.64–2.81) 1.86 (1.42–2.43) 1.80 (1.37–2.36) 3 or more 43 2.60 (1.78–3.79) 2.10 (1.48–2.73) 1.94 (1.42–2.64) A1c, glycated hemoglobin; BMI, body mass index. * Analyses combined using Cox proportional hazard models. † The 1 or more group is compared to 0. The 3 or more group is compared to 0. ‡ Adjustment made using a comorbidity composite scale. SOURCE: Reference 126, copyright © 2009 American Medical Association, reproduced with permission. All rights reserved.

24–12 Diabetes and Cognitive Impairment compliance with diabetes treatment that (113), that peripheral hyperinsulinemia is usually the first step in pharmacologic leads to hypoglycemia, and not the other may impair amyloid clearance in the treatment of type 2 diabetes (141). There way around. The lack of an effect of hypo- brain (47), and that decreased insulin are conflicting data from and animal glycemia on cognition is supported by signaling is a feature of AD brains (130) models suggesting that metformin may an analysis of the DCCT and its follow-up have prompted the testing of diabetes both increase (142) and decrease (143) EDIC study in persons with type 1 medications for the treatment or AD pathology. Retrospective epide- diabetes, who are at high risk of hypogly- prevention of AD dementia. miologic studies are also conflicting, cemic episodes due to insulin treatment suggesting that metformin use is asso- and autonomic dysfunction (103). Severe The thiazolidinediones are powerful insulin ciated with both higher (144,145) and hypoglycemia, which occurred in 40% of sensitizers used in diabetes treatment lower (146) dementia risk. The DPPOS is this cohort, was not related to cognitive (131) and have been tested as possible the largest study to have examined the decline during 18 years of follow-up, drugs to prevent or slow dementing effects of metformin among persons with albeit in relatively young participants. processes. The thiazolidinedione rosiglita- diabetes and those at risk. Metformin zone was tested for secondary prevention exposure over 14.0 years in the DPPOS DIABETES PREVENTION AND of cognitive decline in mild AD dementia was not related to cognition (129), COGNITIVE IMPAIRMENT among 511 persons without diabetes and suggesting at the very least that it is safe The landmark Diabetes Prevention was found to be nonefficacious (68) after from a cognitive standpoint. A pilot trial Program Outcomes Study (DPPOS) promising results in a pilot study of 30 of metformin in 80 persons with amnestic (128), conducted across 25 sites in the persons with mild AD dementia and MCI MCI without treated diabetes (147) United States, measured cognition during (67). However, it seems possible that the showed that persons in the treatment follow-up at two time points 2 years apart negative vascular effects of rosiglitazone arm had better memory performance at (129). The Diabetes Prevention Program, (132) could have eclipsed the beneficial one year compared with placebo (148). the clinical trial preceding the DPPOS, effects on AD pathology (133). The Both the placebo and metformin arms compared lifestyle and metformin inter- thiazolidinedione pioglitazone seems to showed improvement in words recalled ventions with placebo among 3,234 have a lower risk of myocardial infarction in a memory test at one year, but the persons with impaired glucose tolerance compared to rosiglitazone (edema and metformin arm showed a significant and showed that both lifestyle and congestive heart failure are class-specific mean difference of four more words metformin reduced diabetes incidence and not lower) (134). However, a trial recalled (mean recall at baseline was compared to placebo. During the DPPOS, of pioglitazone in 78 adults with MCI 34.2 words in the metformin arm and participants originally randomized to found that pioglitazone improved insulin 36.1 in the placebo arm, p=0.32). These metformin continued the drug, and a resistance, but there was no effect on results needs to be tested in a larger group lifestyle intervention was offered cognitive performance after 6 months clinical trial and should be interpreted to all. Cognition was assessed (n=2,344) (135). It should be noted these drugs have with caution given the small sample size in years 8 and 10 of the DPPOS. Memory concerning side effects, including edema, of the pilot study and the possibility of was assessed with the Spanish English congestive heart failure, and in the case of chance findings. However, these results Verbal Learning Test (SEVLT), the DSST, rosiglitazone, myocardial infarction (136). support those of the DPPOS showing that animal (AF) and letter fluency (LF), and The U.S. Food and Drug Administration metformin is at the very least safe from a a composite score with z scores of these issued a warning indicating that rosigli- cognitive standpoint. tests. Cognition was similar across the tazone carries cardiovascular risks and Diabetes Prevention Program arms in Year restricting its use to patients who cannot Intranasal insulin, used with the purpose 8. However, in mixed models adjusted control their blood glucose by other of increasing brain insulin (not peripheral for age at randomization and assessment means (132). insulin), showed preliminary evidence year, the composite cognitive score was of a cognitive benefit in a pilot study inversely associated with A1c (p=0.0002), Metformin, a of 25 persons with mild AD dementia indicating that while the interventions that belonging to the biguanide class (149) randomized to intranasal insulin or prevented diabetes were not related to (137,138) and the most widely used placebo. Persons in the treatment group cognitive performance, worse glycemia diabetes medication (139), prevents had increased memory savings scores was related to worse cognitive perfor- diabetes by suppressing hepatic glucose compared to persons in the placebo arm. mance cross-sectionally. output, increasing insulin-mediated glucose disposal, increasing intestinal The diabetes medication class of gluca- DIABETES MEDICATIONS AND glucose use, and decreasing fatty acid gon-like peptide agonists (150) increases COGNITIVE IMPAIRMENT oxidation (140). These actions are accom- both insulin secretion and sensitivity and As reviewed above, the findings that panied by reduced pancreatic insulin has been hypothesized to be of benefit in diabetes is related to an increased risk secretion and lower insulin levels in blood AD dementia (151), but this has not been of AD dementia in epidemiologic studies in response to glucose loads. Metformin tested in clinical trials.

24–13 DIABETES IN AMERICA, 3rd Edition

FUTURE DIRECTIONS AND CONCLUSIONS

An extensive body of research ranging needed. Also important is the develop- Establishing causality is important from experimental, clinical, epidemiologic, ment of markers of preclinical cognition because it is necessary to know whether and patient care studies suggests that that can be used as an outcome in trials diabetes treatment and prevention diabetes is associated with cognitive of diabetes treatment and prevention. strategies can be used to prevent impairment from mild to severe forms Another important area for more research dementia. Also, it is important to know and including vascular and neurodegen- is the impact of cognitive impairment whether Alzheimer’s-based dementia erative forms. The association of diabetes on diabetes treatment. New reports of treatment and prevention strategies with vascular and non-amnestic forms an association between diabetes and that are being tested could be useful in of cognitive impairment seems to be dementia continue to suggest increased persons with diabetes, or whether other stronger than that for AD-related and risk of dementia for persons with diabetes. strategies should be pursued. In the amnestic forms of cognitive impairment. However, the causality of this association meantime, the co-occurring epidemics of Elucidating the relation between diabetes has not been established and needs to diabetes and dementia mean that persons and cognitive impairment is still an active be further studied. It is possible that with diabetes are very likely to have area of research in many different fields processes that underlie both diabetes cognitive impairment that will affect their that investigate links among neurodegen- and AD, such as SorCS1 (152), could ability to take care of themselves, which erative, vascular, and metabolic processes. explain a link that is not causal. It is also could result in more adverse dementia Longitudinal studies documenting possible that diabetes decreases brain and diabetes outcomes. This may have a diabetes onset and cognitive performance resilience—that is, the brain’s ability to negative impact on health care systems at earlier ages than in current studies resist neurodegenerative and other brain worldwide. (most of which use elderly cohorts) are insults—but does not directly cause AD.

LIST OF ABBREVIATIONS ACKNOWLEDGMENTS/ FUNDING A1c ...... glycated hemoglobin ACCORD-MIND . . . .Action to Control Cardiovascular Risk in Diabetes-Memory in Dr. Luchsinger’s participation in Diabetes study the writing of this chapter was AD ...... Alzheimer’s disease supported in part by grants from AGE ...... advanced glycation endproduct the American Diabetes Association APOE ...... apolipoprotein E (7-08-CR-41) and the National ARIC ...... Atherosclerosis Risk in Communities Study Institutes of Health (AG026413, DCCT ...... Diabetes Control and Complications Trial AG045334, AG050440, AG051556, DPPOS ...... Diabetes Prevention Program Outcomes Study MD000206, DK048400, and DSST ...... Digital Symbol Substitution Test DK098246). IDEATel ...... Informatics for Diabetes Education and Telemedicine Study LDL ...... low-density lipoprotein MCI ...... mild cognitive impairment PET ...... positron emission tomography DUALITY OF INTEREST RAGE ...... receptor of advanced glycation endproducts Drs. Luchsinger, Ryan, and Launer TBV ...... total brain volume reported no conflicts of interest. VCI ...... vascular cognitive impairment Dr. Luchsinger receives honoraria WMH ...... white matter hyperintensities from Springer for his role as co-editor of the book Diabetes and the Brain. He also receives a stipend from Wolters Kluwer for his CONVERSIONS role as Editor-in-Chief of the journal Conversions for A1c, glucose, and LDL cholesterol values are provided in Diabetes Alzheimer’s Disease and Associated in America Appendix 1 Conversions. Disorders.

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