Prediabetes And Cognition Prediabetic Stages

The progression from normal glucose tolerance to type 2 diabetes is a gradual process which generally proceeds unnoticed. In most cases, the very first changes in insulin and glucose metabolism already occur years before type 2 diabetes is actually diagnosed. Essential to type 2 diabetes is the reduction of insulin sensitivity in the tissue, referred to as insulin resistance (35) (see Chapter 2). Insulin resistance results in a compensatory increase in insulin secretion of the pancreas and abnormal plasma insulin levels, referred to as hyperinsulinemia. Eventually, the pancreas may fail to secrete enough insulin to overcome the insulin resistance and as a consequence insulin-dependent glucose uptake will drop and blood glucose concentrations rise. Depending on the glucose levels at this stage, this is referred to as impaired glucose tolerance or diabetes. Impaired glucose tolerance is defined as fasting blood glucose concentration above normal (6.1mmol/l) and below the diabetic value (7.0mmol/l) as well as a 2-h post-load glucose concentrations between 7.8 and 11.1 mmol/l. Higher fasting blood glucose or 2-h post-load concentrations with diabetes symptoms, such as increased urine output or unusual thirst is classified as diabetes (36). Because insulin resistance, hyperinsulinemia, and impaired glucose tolerance predispose to the development of diabetes in non-diabetic individuals these metabolic abnormalities are often referred to as pre-diabetes. However, not all individuals with insulin resistance or hyperinsulinemia will develop glucose intolerance and diabetes and each condition may occur in isolation.

Insulin resistance and disturbances in glucose metabolism often co-occur with other vascular risk factors such as hypertension, dyslipidemia, and obesity. The co-occurrence of these risk factors is usually referred to as the "the metabolic syndrome." Reaven postulated in 1988 (37) that insulin resistance should be regarded as the central driving force in this syndrome and that traditional vascular risk factors such as hypertension, diabetes, dyslipidemia and, later on, also abdominal obesity are all part of it. Since then, multiple definitions of the syndrome have been postulated, including or excluding different risk factors. The ATP-III criteria are currently the most widely applied (Table 1) (38). The metabolic syndrome predisposes to both atherosclerotic cardiovascular disease and type 2 diabetes and may also be considered a pre-diabetic condition (37, 38).

In the context of this book, which deals with cerebral complications of diabetes, it is important to address the potential impact of these pre-diabetic conditions on the brain. Indeed, several factors that are associated with insulin resistance, glucose intolerance, and the metabolic syndrome

Table 1

Criteria for the metabolic syndrome

ATP-III criteria (SS)

Impaired glucose metabolism

Fasting blood glucose > 6.1 mmol/l or use of insulin/oral glucose-lowering medication


Blood pressure > 130/85 mmHg or use of antihypertensive medication

Elevated triglycerides Low HDL cholesterol

Triglycerides > 1.7 mmol/l

HDL cholesterol <1.3 mmol/l for women and <1.0 mmol/l for men

Abdominal obesity

Waist circumference > 88 cm for women and >102 cm for men

HDL, high-density cholesterol.

are known to be associated with an increased risk of cognitive decline and dementia. In the next section the potential impact of these factors on cognition will be addressed.

Hyperinsulinemia, Glucose Intolerance, and Cognition

Acute rises of peripheral blood glucose and insulin, after, for example, glucose ingestion, may directly influence cognitive performance (see Chapter 18). Indeed, acute improvement of cognitive performance has been reported after ingestion of glucose (39). However, these changes are temporary. The consequences of long-term exposure to elevated blood glucose or insulin levels, which are considered in this chapter, may be quite different.

Population-based studies showed that persons with hyperinsulinemia, but no diabetes, have an increased risk for cognitive decrements compared to persons with normal blood insulin levels (40-43). The cognitive domains mostly affected were memory, attention, and mental flexibility. One study found evidence for greater cognitive decline over a 6-year period for persons with hyperinsulinemia compared to those without (43). The observed effects were at least partially independent of cardiovascular disease, hypertension, and other risk factors associated with the insulin resistance syndrome.

Similar changes are observed in persons with poor glucoregulation. In the studies mentioned here, participants were classified as having impaired glucose tolerance according to the formal definition (36) or an abnormal glucose recovery index after a glucose tolerance test (44). In these studies poor glucoregulation was associated with reduced performance on a variety of cognitive tests, mainly measuring verbal memory (word list and story recall) (41, 44-47). The observed changes in cognitive functioning were relatively small, with effect sizes ranging from 0.1 to 0.2 and thus appear to be somewhat less pronounced than in type 2 diabetes. Not all case-control studies found a relationship between glucose regulation and cognitive performance (48, 49). Only two out of six longitudinal studies found an increased risk for cognitive decline for persons with impaired glucose tolerance at baseline (29, 31, 32, 50-52). However, one of these two studies was the only study that measured glucose tolerance at baseline and during follow-up (50). Cognitive changes in persons with poor glucoregulation are primarily observed in older individuals, although this association is demonstrated in younger adults as well (45, 46).

The Metabolic Syndrome and Cognition

A number of studies have examined cognitive functioning in persons with the metabolic syndrome (53-58). A cross-sectional study showed worse cognitive performance for person with the metabolic syndrome compared to those without on the MMSE and measures of memory, information-processing speed, and fluid intelligence (effect size ^—0.3) (53). Three longitudinal studies that examined the association between the metabolic syndrome and cognitive functioning also showed a 1.2- to 4-fold increased risk of cognitive decline over time (54-56). In contrast, one longitudinal study in a population-based sample of very old persons (>85 years) showed that the metabolic syndrome was actually associated with a decelerated cognitive decline (57), but the implications of this observation are still unclear. Three of the aforementioned studies also reported an interaction with inflammation (54-56), where individuals with the metabolic syndrome and high levels of inflammation were at greatest risk of cognitive impairment.

While the number of studies that assessed cognitive functioning in persons with the metabolic syndrome is still limited, the relation between individual components of the metabolic syndrome, in particular hypertension, and cognitive functioning has been examined more extensively. Cross-sectional studies generally showed a decreased performance for hypertensive persons compared to normotensive individuals in memory, processing speed, and cognitive flexibility (25, 59) with effect sizes that are comparable to those found in studies on cognitive functioning in diabetes. Longitudinal studies tended to show increased risk of cognitive decline (60, 61), although not invariably (62). Interestingly, in these studies an interaction with age is observed where hypertension in midlife was associated with an increased risk of late-life cognitive impairment and dementia, while the link between hypertension at a more advanced age and cognitive functioning was less clear. In fact, some studies showed inverse effects where in old age low blood pressure was actually associated with decreased cognitive performance (63).

Some studies on cognitive functioning in relation to obesity showed worse cognitive performance in persons with a BMI over 25 or 30 kg/m2 (61, 64) compared to normal-weight individuals, but others failed to show such associations (54). Studies that assessed obesity at midlife generally showed a more consistent relation with worse cognitive performance than studies that assessed obesity at late-life. Similar to obesity, the findings of studies on the relation between dyslipidemia and cognition are not always consistent. Some studies reported an increased risk of cognitive impairment associated with high levels of total cholesterol or triglycerides (56, 65), whereas other studies showed inverse associations where high cholesterol was associated with better cognition or low cholesterol with worse cognition (66, 67). For a more detailed overview on the relative impact of each of these vascular risk factors on cognition we refer to two recent reviews from our group (28, 68).

All in all, disturbances in glucose and insulin metabolism and associated vascular risk factors are associated with modest reductions in cognitive performance in "pre-diabetic stages." Consequently, it may well be that the cognitive decrements that can be observed in patients with type 2 diabetes also start to develop before the actual onset of the diabetes. In this regard it is important to note that the size and profile of the cognitive decrements associated with insulin resistance, hyperinsulinemia, impaired glucose tolerance, the metabolic syndrome and its components are similar to each other and to the cognitive decrements found in type 2 diabetes. Because the different vascular and metabolic risk factors that are clustered in the metabolic syndrome are strongly interrelated, the contribution of each of the individual factor will be difficult to assess. Rather than teasing out the individual contributions of risk factors it could be more rewarding to assess shared etiology or consequences, such as atherosclerosis or insulin resistance, and develop treatment strategies directed at these common components.

BRAIN IMAGING IN TYPE 2 DIABETES Structural Changes in Normal Aging

Aging-related changes on brain imaging include vascular lesions and focal and global atrophy. Vascular lesions include (silent) brain infarcts and white-matter hyperintensities (WMHs). WMHs are common in the general population and their prevalence increases with age, approaching 100% by the age of 85 (69). The prevalence of lacunar infarcts also increases with age, up to 5% for symptomatic infarcts and 30% for silent infarcts by the age of 80 (70). In normal aging, the brain gradually reduces in size, which becomes particularly evident after the age of 70 (71). This loss of brain volume is global, including enlargement of the ventricles (subcortical atrophy) and cortical sulci (cortical atrophy). Figure 1 shows examples of these aging-related changes in the brain, which can be detected on computed tomography (CT) or magnetic resonance imaging (MRI).

Global Atrophy The Brain

Fig. 1. White-matter hyperintensities, infarctions, and atrophy of the brain. These MRI images (FLAIR-sequence) show typical age-related changes of the brain that are often relatively more pronounced in older patients with type 2 diabetic. The picture on the left shows punctuate deep (left arrow) and periventricular (right arrow) white-matter hyperintensities. The middle picture shows subcortical lacunar infarctions and enlarged ventricles. The picture on the right shows global cortical atrophy.

Fig. 1. White-matter hyperintensities, infarctions, and atrophy of the brain. These MRI images (FLAIR-sequence) show typical age-related changes of the brain that are often relatively more pronounced in older patients with type 2 diabetic. The picture on the left shows punctuate deep (left arrow) and periventricular (right arrow) white-matter hyperintensities. The middle picture shows subcortical lacunar infarctions and enlarged ventricles. The picture on the right shows global cortical atrophy.

Brain Imaging in Patients with Type 2 Diabetes and Pre-diabetic Stages

Population-based studies reported an increased prevalence and incidence of lacunar infarcts in patients with type 2 diabetes (70, 72-74). A recent systematic review showed that patients with diabetes have a 2-fold increased risk of (silent) infarcts compared to non-diabetic persons (75). The relationship between type 2 diabetes and WMHs is subject to debate. Several large population-based studies did not observe a significant association between diabetes and WMHs (75-77). The use of relatively crude, insensitive WMH rating scales may explain some of the inconsistencies. Recent case-control studies that applied a more refined WMH rating scale and volumetric measurements reported a modest increase in WMH severity in patients with type 2 diabetes (78-81), and there are now clear indications that diabetes is a risk factor for WMH progression (82).

Brain atrophy can be assessed with relatively simple measures such as ordinal rating scales or one-dimensional ventricle-to-brain ratios or more sophisticated techniques such as fully automated volumetry. Modest degrees of global atrophy have been demonstrated in patients with type 2 diabetes with each of these techniques (75, 83, 84). Given the association between type 2 diabetes and Alzheimer's disease (see also Chapter 13) atrophy in specific brain regions such as the medial temporal lobe is of particular interest. Some population-based studies have indeed shown that type 2 diabetes was associated with reduced hippocampal and/or amygdalar volumes on MRI (77, 85) and a 3-fold increased risk of severe medial temporal lobe atrophy (74). Although abnormalities in hippocampal volume may be an early manifestation of brain atrophy in type 2 diabetes (86), it is not yet clear whether temporal lobe structures are particularly vulnerable to diabetes-related atrophy.

To date, the number of studies that specifically addressed the relation between brain abnormalities and cognitive functioning in patients with type 2 diabetes is limited. Some studies showed that, within a group of patients with type 2 diabetes, cognitive functioning was related to white-matter hyperintensities, atrophy, and the presence of infarcts (78, 87). Another study observed an independent association between periventricu-lar white-matter lesion and motor speed, but no association between other MRI measures and cognitive performance (9).

Some evidence exists that the aforementioned brain imaging abnormalities start to develop in the pre-diabetic stage. One study found that reduced peripheral glucose regulation was not only associated with smaller hippocampal volume, but also with decreased general cognitive performance and memory performance in healthy elderly (47). Moreover, hyperinsulinemia, impaired glucose tolerance, insulin resistance, and the metabolic syndrome are previously reported as risk factors for lacunar infarcts, atrophy, and white-matter hyperintensities (77, 88-91). WMHs and infarcts have also been associated with diabetes-related complications such as retinal microvascular disease (92) and microalbuminuria (91). However, there are inconsistencies between studies, possibly partially due to confounding effects of other associated risk factors.

Vascular risk factors that are closely related to diabetes, such as hypertension, dyslipidemia, and obesity, have been examined in more detail in relation to abnormalities on brain MRI. Hypertension is one of the most important risk factors for stroke in the general population (70) and is also strongly associated with WMHs (93). Dyslipidemia is also strongly associated with stroke, but associations with lacunar infarcts, WMHs, or atrophy are less clear (89, 94, 95). Obesity appears to be associated with reduced global brain volume and hippocampal volume (96,97). Some studies showed an independent relationship between obesity and lacunar infarcts (88) and WMHs (98), but others failed to show such associations (72, 90).

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