Claude Messier

The Relationship between Impaired Glucose Tolerance, Type 2 Diabetes, and Cognitive Function

ABSTRACT The present review integrates findings of published studies that have evaluated the cognitive function of treated and untreated type 2 diabetic patients and provides a detailed overview of the neuropsychological assessments conducted. Cognitive deficits are observed in older people with glucose intolerance or untreated diabetes but these deficits appear to be attenuated by treatments that improve glycemic control. Cognitive decrements in treated type 2 diabetic patients are most consistently observed on measures of verbal memory (35% of the measures) and processing speed (45% of the measures) while preserved function is observed on measures of visuospatial, attention, semantic and language function. Some studies suggest that deficits in cognitive functions are associated with poorer glycemic control. A number of other factors, such as depression, cardiovascular and cerebrovascular disease, increase these deficits. We conclude that, in diabetic patients who achieve and maintain good glycemic control, type 2 diabetes only has a small impact on cognitive functions before the age of 70 years. However, early onset of type 2 diabetes, poor glycemic control and the presence of micro- and macrovascular disease may interact to produce early cognitive deficits. In older adults (70 years and over), diabetes likely interacts with other dementing processes such as vascular disease and Alzheimers disease to hasten cognitive decline.

Impact of impaired glucose tolerance and type 2 diabetes on cognitive aging

Type 2 diabetes is becoming increasingly common in most Westernized countries and it now occurs at a younger age. There are pathologies associated with diabetes, mostly systemic ones. However, a growing number of studies is also showing that diabetes is associated with impaired cognitive processes in older adults and hasten the progression to dementia. The most common cognitive deficits are decreases in processing speed and verbal memory; these may extend to other aspects of cognition with increasing age. The link between diabetes and cognitive decline is obscured by depression, hypertension, as well as cardio- and cerebrovascular diseases, all of which occur to varying degrees in diabetic patients. A few studies indicate that controlling blood glucose with anti-diabetic treatments may help prevent the cognitive decline in diabetic patients before they are 70 years old. After that age, diabetes appears to produce faster cognitive decline and may increase the occurrence of pathological changes associated with vascular dementia or Alzheimers disease.

Immunohistochemical localization and quantification of glucose transporters in the mouse brain

A family of seven facilitative glucose transporters (Glut1-5, 7 and 8) mediates the cellular uptake of glucose. In the brain, Glut2, Glut5 and Glut8 are found at relatively low levels whereas Glut1, Glut3 and Glut4 were reported in abundance in several brain regions. Using immunofluorescence, this study investigated, compared and quantified the localization of the brain major glucose transporters, Glut1, Glut3 and Glut4, in the different cerebral areas of CD1 mice. Most of the staining of Glut1, Glut3 and Glut4 in the mouse brain coincides with observations made in rats. The results confirm the cortical neuropil distribution of Glut3, the prominence of this transporter in the mossy fiber field of the hippocampus and the Glut3 and Glut4 immunostaining of the hippocampal pyramidal cell layer. The present study also reports novel localizations of the transporters such as the presence of Glut3 in neuronal perikarya, Glut4-labeled neurons in the CA3 of the hippocampus and the subiculum. In the cerebellum, Glut3 shows subcellular localization to the base of the Purkinje cell bodies near the axon hillock. Furthermore, an important population of Golgi cells was found to be strongly immunostained for Glut4 in the granular cell layer of the cerebellum. The quantification results suggest that the relative abundance of Glut1 in the frontal and motor cortices coincides well with the high-energy demands of these brain regions. However, the Glut4-selective abundance in cerebral motor areas supports its suggested role in providing the energy needed for the control of the motor activity. The reported neuropil distribution of Glut3 seems to uphold its suggested role in synaptic energy provision and neurotransmitter synthesis. We conclude that the cellular and regional distributions of the glucose transporters in the rodent brain seem to be relevant to their corresponding functions.

Effect of Glucose and Peripheral Glucose Regulation on Memory in the Elderly

We examined changes in cognitive performance following the intake of a glucose (50 g) or saccharin solution (50 mg) in fasted elderly male and female subjects. Glucoregulation was estimated using a recovery index that was used to categorize subjects within each sex as having poor or good recovery. Elderly males with poor recovery performed worse on the Logical Memory subtest of the Wechsler Memory Scale and on the free recall or recognition parts of a work list task. The item analysis of the Logical Memory subtest showed that male subjects with poor recovery remembered less of the last items of the paragraphs after drinking saccharin while the first items were equally remembered by both groups. Glucose improved the performance of the males with good regulation for the first seven items while the performance of males with poor regulation decreased for those items under glucose. The present study support the notion that peripheral glucoregulation can influence memory performance and that the ingestion of glucose can influence certain aspects of memory functioning.

Effect of age and glucoregulation on cognitive performance

Non-insulin dependent diabetes mellitus (NIDDM) has been associated with a number of physiological consequences including neuropathy, retinopathy and incidence of vascular disease. Recently, several authors reviewed studies that suggested that NIDDM is associated with cognitive impairments leading to a higher incidence of dementia. In the present experiment, we measured cognitive function in 57 healthy male and female non-diabetic older participants who ranged in age from 55 to 84. Various biological measures were obtained including a glucose tolerance test during which glucose and insulin were measured. Participants were separated into better and poorer glucoregulatory groups on the basis of their blood glucose levels during the tolerance test. Participants were evaluated twice, once after drinking a saccharin solution and on another occasion after drinking a glucose solution (50 g). Older participants (72 years and over) with poorer glucoregulation had the worse performance in tests evaluating working memory, verbal declarative memory and executive functions. Glucose administration appeared to only attenuate the decrements observed in the saccharin condition in the older participants for some of the tests. These results suggest that cognitive functions may be impaired before glucoregulatory impairment reaches levels consistent with a type II diabetes diagnosis.

Diabetes, Alzheimer's disease and apolipoprotein genotype.

Non-insulin dependent diabetes mellitus (NIDDM) has been associated with a number of physiological consequences including neuropathy, retinopathy and incidence of vascular disease. Recently, several authors reviewed studies that suggested that NIDDM is associated with cognitive impairments leading to a higher incidence of dementia and Alzheimers disease. The current diagnostic practices that typically exclude from an AD diagnostic any patients with suspected vascular dementia, makes it very hard to resolve this issue and likely result in an underestimation of the number of people with Alzheimers disease and diabetes. When people with cerebrovascular disease are included, diabetes is associated with an increased risk for Alzheimers disease. Studies that have examined peripheral glucoregulation in Alzheimers disease are not consistent but some show small to moderate impairments in insulin sensitivity. One recent study suggest that in people that have both diabetes and an ApoE4 allele, the risk of developing Alzheimers disease is more than double the risk of people with an ApoE4 allele without diabetes. Although diabetes does not produce any of the usual brain pathology associated with Alzheimers disease, one study has shown that diabetes dramatically increases the amyloid deposition and neurofibrillary tangles in people with the ApoE4 genotype. Taken together, the data available suggest that diabetes is probably a risk factor for Alzheimers disease mainly through the cerebrovascular disease diabetes causes. In people with other risk factors such as ApoE4 allele, diabetes appears to lead to a more dramatic increase in Alzheimers disease pathology.

Effect of glucose, glucose regulation, and word imagery value on human memory.

Changes in memory performance were examined after intake of a glucose (50 g) or saccharin (50 mg) solution in fasted men and women. Glucoregulation was estimated by using a recovery index to categorize participants within each gender as having poor or good recovery. Memory was assessed with word-learning tasks in which the imagery-evoking value of the words was systematically manipulated to yield high- and low-imagery lists. The results showed that men and women characterized as having poor glucose regulation had significantly worse memory performance under the saccharin condition. This decrement was reversed by glucose ingestion. These effects were observed for both low- and high-imagery words. This study supports the hypothesis that poor glucoregulation is associated with poor memory performance even in young healthy participants and that the ingestion of glucose can improve their memory.

Longitudinal study of the effects of a high-fat diet on glucose regulation, hippocampal function, and cerebral insulin sensitivity in C57BL/6 mice.

Although the increasing rate of obesity has stimulated interest in the effects of diet composition on peripheral systems, comparatively little work has been done to examine effects upon the brain. A diet high in fat is one of many factors that can promote obesity, and previous research has shown that such a diet can produce learning and memory impairment in rodents. In the present study, C57BL/6 mice were placed on either a high-fat (45% kcal fat) or regular (5% kcal fat) diet, and examined at different points during the subsequent year. The high-fat diet led to increased weight gain, significant impairment in glucoregulation, and altered insulin-mediated signaling within the hippocampus, an area of the brain believed to be important for the acquisition of memory. Following ten months on either diet, synaptic function in ex vivo hippocampal slices was examined, and neither stimulus-response curves nor electrically induced long-term potentiation were found to be different. As well, performance in the Morris water maze, a hippocampal-dependent test of spatial memory, was not influenced by diet. However, mice consuming a high-fat diet failed to perform an operant bar-pressing task, indicating a significant impairment to procedural learning and consolidation processes. Despite causing broad peripheral changes in C57BL/6 mice, consuming a large proportion of calories from saturated fat had only a limited effect upon learning and memory, which suggests that certain aspects of brain function are selectively vulnerable to the influences of diet.

Ethological confirmatory factor analysis of anxiety-like behaviour in the murine elevated plus-maze

The elevated plus-maze has been used in animal research to measure anxiety since 1985 and is currently the most widely used animal model of anxiety. Since this paradigm has been the subject of several principal components analyses, it is well qualified for confirmatory factor analysis research. The current report builds on the substantial theoretical knowledge and empirical data obtained from these structural analyses with a view to obtain further progress in the evolution of our understanding of animal anxiety in the elevated plus-maze. The purpose of the present report was two-fold: (a) to test if the a piori imposition of a 3-factor model, or a competing 2-factor elevated plus-maze model, would fit our sample (n=200 CD-1 mice) data in each of two trials within an inferential confirmatory factor analytic framework; (b) provide a well-fitting model that confers indicator variables that can most effectively and parsimoniously measure underlying constructs of elevated plus-maze behaviour. Multiple model-fitting criteria were used, and issues related to data non-normality, outliers, replicability of the model, sampling error and error of approximation in the estimation of final model fit were addressed. The final 2-factor model, with estimated error covariance between two different pairs of indicator variables, was a good fit on the trial-1 data, although it was necessary to allow unprotected stretch attends to non-significantly cross-load on factor-2. A 2-factor model also fit the trial-2 data from the present analysis, although it was necessary to allow closed arm time ratio to negatively cross-load on factor-1. These results indicate that inferential hypothesis testing and model building procedures within a confirmatory factor analysis framework produces interpretable animal anxiety indices in the elevated plus-maze. Moreover, a 2-factor, rather than a 3-factor model, parsimoniously and unambiguously explained the underlying constructs of anxiety-like mouse behaviour in the elevated plus-maze in the present study. Taken together, a reduction in the growing number of behavioural indices reported in elevated plus-maze pharmacological studies is suggested.

Measuring the impact of exercise on cognitive aging: methodological issues

Physical exercise and fitness have been proposed as potential factors that promote healthy cognitive aging. Support for this hypothesis has come from cross sectional, longitudinal, and intervention studies. In the present review, we discuss several methodological problems that limit the conclusions of many studies. The lack of consensus on how to retrospectively measure exercise intensity is a major difficulty for all studies that attempt to estimate lifelong impact of exercise on cognitive performance in older adults. Intervention studies have a much better capacity to establish causality, but still suffer from difficulties arising from inadequate control groups and the choice and modality of administration of cognitive measures. We argue that, while the association between exercise and preserved cognition during aging is clearly demonstrated, the specific hypothesis that physical exercise is a cause of healthy cognitive aging has yet to be validated. A number of factors could mediate the exercise-cognition association, including depression, and social or cognitive stimulation. The complex interactions among these 3 factors and the potential impact of exercise on cognition remain to be systematically studied. At this time, the best prescription for lifestyle interventions for healthy cognitive aging would be sustained physical, social, and mental activities. What remains unknown is which type of activity might be most useful, and whether everyone benefits similarly from the same interventions.