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DIABETES and COGNITIVE IMPAIRMENT José A CHAPTER 24 DIABETES 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 prediabetes 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 brain of hyperglycemia or the effects of the diabetes-associated comorbidities, such as hypertension, 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. Type 1 diabetes is, in general, related to modest decrements in cognitive abilities, primarily in executive-frontal abilities. Type 2 diabetes 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 glucose control on cognition 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 memory 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 disease (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 memories. 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 risk factor 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
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