G.J. Biessels

Cognition and synaptic plasticity in diabetes mellitus

Diabetes mellitus is associated with cognitive deficits and an increased risk of dementia, particularly in the elderly. These deficits are paralleled by neurophysiological and structural changes in the brain. In animal models of diabetes, impairments of spatial learning occur in association with distinct changes in hippocampal synaptic plasticity. At the molecular level these impairments might involve changes in glutamate-receptor subtypes, in second-messenger systems and in protein kinases. The multifactorial pathogenesis of diabetic encephalopathy is not yet completely understood, but clearly shares features with brain ageing and the pathogenesis of diabetic neuropathy. It involves both metabolic and vascular changes, related to chronic hyperglycaemia, but probably also defects in insulin action in the brain. Treatment with insulin might therefore not only correct hyperglycaemia, but could also directly affect the brain.

Place Learning and Hippocampal Synaptic Plasticity in Streptozotocin-Induced Diabetic Rats

Moderate impairment of learning and memory has been recognized as a complication of diabetes. The present study examined behavioral and electrophysiological measures of cerebral function in streptozotocin (STZ)-induced diabetic rats. Behavioral testing consisted of a spatial learning task in a water maze. Electrophysiological testing consisted of in vitro assessment of hippocampal long-term potentiation (LTP), an activity-dependent form of synaptic plasticity, which is believed to be related to the cellular mechanisms of learning and memory. Two experiments were performed: the first with severely hyperglycemic rats and the second with moderately hyperglycemic rats. Rats were tested in the water maze 11 weeks after induction of diabetes. Next, LTP was measured in vitro in trained animals. Both spatial learning and LTP expression in the CA1 field of the hippocampus were impaired in severely hyperglycemic rats as compared with nondiabetic controls. In contrast, spatial learning and hippocampal LTP were unaffected in moderately hyperglycemic rats. The association of alterations in hippocampal LTP with specific learning impairments has previously been reported in conditions other than diabetes. Our findings suggest that changes in LTP-like forms of synaptic plasticity in the hippocampus, and possibly in other cerebral structures, are involved in learning deficits in STZ-induced diabetes. The beneficial effect of moderate glycemic control on both place learning and hippocampal LTP supports the significance of the relation between these two parameters and indicates that the development of the observed deficits may be related to the level of glycemic control.

Water maze learning and hippocampal synaptic plasticity in streptozotocin diabetic rats: effects of insulin treatment

Streptozotocin-diabetic rats express deficits in water maze learning and hippocampal synaptic plasticity. The present study examined whether these deficits could be prevented and/or reversed with insulin treatment. In addition, the water maze learning deficit in diabetic rats was further characterized. Insulin treatment was commenced at the onset of diabetes in a prevention experiment, and 10 weeks after diabetes induction in a reversal experiment. After 10 weeks of treatment, insulin-treated diabetic rats, untreated diabetic rats and non-diabetic controls were tested in a spatial version of the Morris water maze. Next, hippocampal long-term potentiation (LTP) was measured in vitro. To further characterize the effects of diabetes on water maze learning, a separate group of rats was pre-trained in a non-spatial version of the maze, prior to exposure to the spatial version. Both water maze learning and hippocampal LTP were impaired in diabetic rats. Insulin treatment commenced at the onset of diabetes prevented these impairments. In the reversal experiment, insulin treatment failed to reverse established deficits in maze learning and restored LTP only partially. Non-spatial pre-training abolished the performance deficit of diabetic rats in the spatial version of the maze. It is concluded that insulin treatment may prevent but not reverse deficits in water maze learning and LTP in streptozotocin-diabetic rats. The pre-training experiment suggests that the performance deficit of diabetic rats in the spatial version of the water maze is related to difficulties in learning the procedures of the maze rather than to impairments of spatial learning.

Cerebral function in diabetes mellitus

SummaryDiabetes mellitus is a common metabolic disorder associated with chronic complications such as nephropathy, angiopathy, retinopathy and peripheral neuropathy. Diabetes is not often considered to have deleterious effects on the brain. However, long-term diabetes results in a variety of subtle cerebral disorders, which occur more frequently than is commonly believed. Diabetic cerebral disorders have been demonstrated at a neurochemical, electrophysiological, structural and cognitive level; however, the pathogenesis is still not clear. Probably alterations in cerebral blood supply and metabolic derangements play a role, as they do in the pathogenesis of diabetic neuropathy. Furthermore, the brain is also affected by recurrent episodes of hypoglycaemia and poor metabolic control. We describe herein the cerebral manifestations of diabetes and discuss the putative pathogenetic mechanisms.

Learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: interaction of diabetes and ageing

AbstractAims/hypothesis. Diabetes mellitus leads to functional and structural changes in the brain which appear to be most pronounced in the elderly. Because the pathogenesis of brain ageing and that of diabetic complications show close analogies, it is hypothesized that the effects of diabetes and ageing on the brain interact. Our study examined the effects of diabetes and ageing on learning and hippocampal synaptic plasticity in rats.¶Methods. Young adult (5 months) and aged (2 years) rats were examined after 8 weeks of streptozotocin-diabetes. Learning was tested in a Morris water maze. Synaptic plasticity was tested ex vivo, in hippocampal slices, in response to trains of stimuli of different frequency (0.05 to 100 Hz).¶Results. Statiscally significant learning impairments were observed in young adult diabetic rats compared with controls. These impairments were even greater in aged diabetic animals. In hippocampal slices from young adult diabetic animals long-term potentiation induced by 100 Hz stimulation was impaired compared with controls (138 vs 218 % of baseline). In contrast, long-term depression induced by 1 Hz stimulation was enhanced in slices from diabetic rats compared with controls (79 vs 92 %). In non-diabetic aged rats synaptic responses were 149 and 93 % of baseline in response to 100 and 1 Hz stimulation, compared with 106 and 75 % in aged diabetic rats.¶Conclusion/interpretation. Both diabetes and ageing affect learning and hippocampal synaptic plasticity. The cumulative deficits in learning and synaptic plasticity in aged diabetic rats indicate that the effects of diabetes and ageing on the brain could interact. [Diabetologia (2000) 43: 500–506]

The metabolic syndrome is associated with decelerated cognitive decline in the oldest old

Background: The metabolic syndrome is a cluster of risk factors including hypertension, obesity, dyslipidemia, and impaired glucose metabolism, associated with cardiovascular disease. The metabolic syndrome also appears to predispose to cognitive dysfunction and dementia. In this study the association between the metabolic syndrome and cognitive function was examined in a population of the oldest old. Methods: The Leiden 85-Plus Study is a population-based study of 599 persons from age 85 onward. Cognitive function was assessed annually from age 85 to 90 by means of four neuropsychological tests. The presence (n = 237) or absence (n = 325) of the metabolic syndrome was recorded at baseline. Cross-sectional and prospective associations between the metabolic syndrome and cognitive function were analyzed with linear mixed models, adjusted for sex and level of education. Results: At age 85 the metabolic syndrome was not associated with lower cognitive performance. The metabolic syndrome was associated with a decelerated cognitive decline from age 85 to 90 on the Mini-Mental State Examination (additional annual effect 0.18 [0.07], p = 0.01), the Stroop Test (−1.49 [0.59], p = 0.01), and the Letter Digit Coding Test (0.26 [0.09], p = 0.005). This effect was mainly attributable to glucose, body mass index, and, to a lesser extent, blood pressure. Conclusion: The association between the metabolic syndrome and accelerated cognitive decline, which has been reported in persons up to age 75, is not evident in a population of the oldest old. The concept of the metabolic syndrome may be less valid in this age group.

Hippocampal synaptic plasticity in streptozotocin-diabetic rats: impairment of long-term potentiation and facilitation of long-term depression

Streptozotocin-diabetic rats, an animal model for diabetes mellitus, show learning deficits and impaired long-term potentiation in the CA1-field of the hippocampus. The present study aimed to further characterize the effects of streptozotocin-diabetes on N-methyl-D-aspartate receptor-dependent long-term potentiation in the CA1-field, to extend these findings to N-methyl-D-aspartate receptor-dependent and independent long-term potentiation in other regions of the hippocampus and to examine effects on long-term depression. First, the effect of diabetes duration on long-term potentiation in the CA1-field was determined. A progressive deficit was observed after a diabetes duration of six to eight weeks, which reached a maximum after 12 weeks of diabetes and remained stable thereafter. Next, long-term potentiation was examined in the dentate gyrus and in the CA3-field after 12 weeks of diabetes. Both were found to be impaired compared to controls. Finally, long-term depression was examined in the CA1-field of the hippocampus after 12 weeks of diabetes and found to be enhanced in slices from diabetic rats compared to controls. Changes in synaptic plasticity were observed in hippocampal slices from streptozotocin-diabetic rats. Expression of N-methyl-D-aspartate receptor-dependent long-term potentiation was impaired in the CA1-field and dentate gyrus and expression of N-methyl-D-aspartate receptor-independent long-term potentiation was impaired in the CA3-field. In contrast, expression of long-term depression was facilitated in CA1. It is suggested that this combination of changes in plasticity may reflect alterations in intracellular signalling pathways.

Voxel-based morphometry demonstrates reduced grey matter density on brain MRI in patients with diabetic retinopathy

Aims/hypothesisIn addition to nephropathy, retinopathy and peripheral neuropathy, a microvascular complication of type 1 diabetes that may be tentatively referred to as ‘diabetic encephalopathy’ has gained increasing attention. There is growing evidence that lowered cognitive performance in patients with type 1 diabetes is related to chronic hyperglycaemia rather than recurrent episodes of severe hypoglycaemia, as previously speculated. The aim of our study was to use magnetic resonance imaging (MRI) to establish whether long-term hyperglycaemia, resulting in advanced retinopathy, contributes to structural changes in the brain (reduced grey matter).Subjects, materials and methodsWe applied voxel-based morphometry on magnetic resonance images to compare grey matter density (GMD) between three groups of participants. GMD is used as a marker of cortical atrophy. We compared 13 type 1 diabetic patients with a microvascular complication (i.e. proliferative retinopathy) with 18 type 1 diabetic patients who did not have retinopathy in order to assess the effects of microvascular changes on GMD. Both patient groups were compared with 21 healthy control subjects to assess the effect of diabetes in itself.ResultsPatients with diabetic retinopathy showed reduced GMD in the right inferior frontal gyrus and right occipital lobe compared both with patients without retinopathy and with healthy controls (p<0.05).Conclusions/interpretationOur data show that patients with type 1 diabetes, who, as a consequence of chronic hyperglycaemia, had developed advanced retinopathy, also showed increased focal cortical atrophy on brain MRI.

Diabetic encephalopathy: a concept in need of a definition

Diabetes mellitus is associated with the occurrence of welldescribed microvascular complications, including retinopathy, nephropathy and peripheral neuropathy. The concept of central neuropathy has been controversial for more than 80 years now. As early as 1922 it was recognised that diabetes can lead to cognitive dysfunction [1]. The prevalence of cognitive dysfunction is difficult to estimate as it depends heavily on the way it is assessed. The reported prevalence is about 40% in long-standing or poorly controlled diabetes [2]. Cognitive dysfunction in diabetes is characterised by lowered performance on several cognitive domains, most notably slowing of mental speed and diminished flexibility [3]. The magnitude of these cognitive deficits appears mild to moderate, but can significantly hamper daily functioning, adversely affecting quality of life [4]. Cognitive decline in diabetic patients treated with insulin has so far largely been attributed to recurrent episodes of hypoglycaemia, rather than to hyperglycaemia, although there is little evidence to support this notion [5, 6]. In trying to describe cognitive impairment in diabetes as a complication of the disease, the term ‘diabetic encephalopathy’ was introduced in 1950 [7]. In 1965, rather characteristic pathological changes were found in brains from 16 long-term juvenile diabetic patients who had died from vascular complications of diabetes [8]: diffuse degenerative abnormalities, pseudocalcinosis, severe angiopathy of cerebral vessels, atrophy of the dentate nucleus, demyelinisation of cranial nerves and fibrosis of the leptomeninges. The authors stated that this histological pattern justifies the term ‘diabetic encephalopathy’, because it differs from that seen in any other clinical condition. However, for several reasons, the term ‘encephalopathy’ has not been widely accepted. Firstly, it has strong negative connotations and does not seem to match the mild cognitive problems usually seen in (nondemented) diabetic patients. Secondly, and most importantly, the diagnosis diabetic encephalopathy lacks clear criteria and is therefore difficult to ascertain. Historically, the term diabetic encephalopathy applies to type 1 diabetic patients only. Other terms found in the literature to describe cognitive dysfunction in diabetes include functional cerebral impairment and central neuropathy. To facilitate research into this area and to increase recognition of the disorder, we propose a new term—‘diabetes-associated cognitive decline’ (DACD). This term is not suggestive of a particular pathogenesis, but merely describes a state of mild to moderate cognitive impairment, in particular psychomotor slowing and reduced mental flexibility, not attributable to other causes. Pathogenic research should focus on type 1 diabetes patients first, as in type 2 diabetes bias is introduced by several coexistent risk factors for cognitive dysfunction other than hyperglycaemia (e.g. hypertension, hyperlipidaemia). For further validation of the term DACD, we propose the operational research criteria summarized in the text box. As the relation between cognitive complaints and objective dysfunction is weak, we do not regard subjective complaints about cognitive functioning as a prerequisite for diagnosis of DACD. As cognitive dysfunction in type 1 diabetes is usually mild to G. S. Mijnhout . M. Diamant . S. Simsek . R. J. Heine Department of Endocrinology and Diabetes, VU University Medical Centre, Amsterdam, The Netherlands

Effects of streptozotocin-diabetes on the hippocampal NMDA receptor complex in rats

In animal models of diabetes mellitus, such as the streptozotocin‐diabetic rat (STZ‐rat), spatial learning impairments develop in parallel with a reduced expression of long‐term potentiation (LTP) and enhanced expression of long‐term depression (LTD) in the hippocampus. This study examined the time course of the effects of STZ‐diabetes and insulin treatment on the hippocampal post‐synaptic glutamate N‐methyl‐d‐aspartate (NMDA) receptor complex and other key proteins regulating hippocampal synaptic transmission in the post‐synaptic density (PSD) fraction. In addition, the functional properties of the NMDA‐receptor complex were examined. One month of STZ‐diabetes did not affect the NMDA receptor complex. In contrast, 4 months after induction of diabetes NR2B subunit immunoreactivity, CaMKII and Tyr‐dependent phosphorylation of the NR2A/B subunits of the NMDA receptor were reduced and αCaMKII autophosphorylation and its association to the NMDA receptor complex were impaired in STZ‐rats compared with age‐matched controls. Likewise, NMDA currents in hippocampal pyramidal neurones measured by intracellular recording were reduced in STZ‐rats. Insulin treatment prevented the reduction in kinase activities, NR2B expression levels, CaMKII–NMDA receptor association and NMDA currents. These findings strengthen the hypothesis that altered post‐synaptic glutamatergic transmission is␣related to deficits in learning and plasticity in this animal model.