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Biomedical subjects

G J Biessels

Publications and source records attributed to G J Biessels.

At least 19 recordsLinked to original sources
PubMed2006

The impact of diabetes mellitus on cognitive decline in the oldest of the old: a prospective population-based study.

AIMS/HYPOTHESIS: Diabetes mellitus is a risk factor for the development of cognitive impairment and dementia in the general population up to 75 years of age. As part of the Leiden 85-plus Study we studied the effects of diabetes on cognition in the oldest old. SUBJECTS AND METHODS: The Leiden 85-plus Study is a prospective population-based study of 599 persons from age 85 onward. Cognitive function was assessed each year from ages 85 to 90 by means of four neuropsychological tests. The presence of diabetes and vascular disease was recorded at baseline, HbA(1c) was assessed by means of a blood sample at ages 85 and 90. The cross-sectional and prospective associations between diabetes and cognitive function were analysed with linear mixed models, adjusted for sex and level of education. RESULTS: At age 85, diabetes was associated with a lower level of cognitive functioning on the Letter Digit Coding test and the Stroop Test. Diabetes was not associated with accelerated cognitive decline during follow-up. Within the group of diabetic patients, macrovascular disease was the most important determinant of cognitive dysfunction. CONCLUSIONS/INTERPRETATION: The association between diabetes and accelerated cognitive decline, which has been documented previously in patients up to 75 years of age, may be less evident after age 85. This suggests that the damage occurs in previous years and that therapies aimed at preventing cognitive decline and dementia should focus on the younger old.

Aged, 80 and over↗
PubMed2006

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

AIMS/HYPOTHESIS: In 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 METHODS: We 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. RESULTS: Patients 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/INTERPRETATION: Our 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.

Adult↗
PubMed2006

Cerebrovascular reserve capacity is preserved in a population-based sample of patients with type 2 diabetes mellitus.

BACKGROUND AND PURPOSE: Type 2 diabetes mellitus (DM2) is associated with an increased risk of stroke. DM2 is also associated with cognitive impairments. Vascular dysfunction, such as impaired cerebrovascular reserve capacity (CVR), may be a determinant of these changes, but previous studies on CVR in DM2 have provided variable results in selected populations of patients. We aimed to examine CVR in a population-based sample of DM2 patients. METHODS: The CO(2) reactivity of the middle cerebral artery was examined using transcranial Doppler ultrasonography in 81 DM2 patients and 38 controls. In DM2 patients CVR was correlated with diabetic parameters, vascular risk factors and cognitive functioning. RESULTS: CVR was similar in patients and controls (51 vs. 49%). Within the DM2 group, there was no statistically significant relationship between CVR and DM duration, HbA(1c), albuminuria, blood pressure, intima-media thickness and cognition. CVR tended to be lower in diabetic patients with retinopathy [46 vs. 55%, mean difference: -7.9 (confidence interval -18.0, 2.2)]. CONCLUSION: We conclude that CVR is not impaired in unselected patients with DM2 and probably does not, therefore, play a major role in the aetiology of cognitive impairment.

Aged↗
PubMed2006

Increased cortical atrophy in patients with Alzheimer's disease and type 2 diabetes mellitus.

BACKGROUND: The risk of Alzheimer's disease (AD) is increased in type 2 diabetes (DM2). This increased risk has been attributed to vascular comorbidity, but other mechanisms, such as accelerated ageing of the brain, have also been implicated. OBJECTIVE: To determine whether AD in patients with DM2 is associated with an increased occurrence of vascular lesions in the brain, by increased cerebral atrophy, or a combination of both. METHODS: In total, 29 patients with AD and DM2 and 58 patients with AD and without DM2 were included in the study. Clinical characteristics were recorded, and a neuropsychological examination and magnetic resonance imaging (MRI) scan were performed. MRI scans were rated for cortical and subcortical atrophy, medial temporal lobe atrophy, white matter lesions, and infarcts. RESULTS: The neuropsychological profiles of the two groups were identical. Patients with AD and DM2 had increased cortical atrophy on MRI (p<0.05) compared with the non-DM2 group. In addition, infarcts were more common (odds ratio 2.4; 95% CI 0.8 to 7.8), but this effect did not account for the increased atrophy. The other MR measures did not differ between the groups. CONCLUSION: The results suggest that non-vascular mechanisms, leading to increased cortical atrophy, are also involved in the increased risk of AD in DM2.

Aged↗
PubMed2006

Type 2 diabetes, cognitive function and dementia: vascular and metabolic determinants.

Type 2 diabetes is a common metabolic disease with a rising global prevalence. It is associated with slowly progressive end-organ damage in the eyes and kidneys, but also in the brain. The latter complication is often referred to as "diabetic encephalopathy" and is characterized by mild to moderate impairments in cognitive functioning. It is also associated with an increased risk of dementia. To date, its pathogenetic mechanisms are largely unclear. Cognitive impairments in patients with type 2 diabetes have been associated both with vascular risk factors, such as hypertension and dyslipidemia, and with diabetes-related factors, such as glycemic control, duration of the disease and treatment modality. Studies that address these associations generally focus on statistical (in)dependence of certain risk factors in the association between type 2 diabetes and cognitive decline rather than the causality of the association, which, from a mechanistic point of view, is more relevant. In this review we describe the association between type 2 diabetes and cognitive dysfunction and dementia. Furthermore, potential determinants of impaired cognition in type 2 diabetes are addressed both from the perspective of statistical associations and from a mechanistic point of view.

Brain↗
PubMed2005

Increased risk of Alzheimer's disease in Type II diabetes: insulin resistance of the brain or insulin-induced amyloid pathology?

Type II diabetes mellitus (DM2) is associated with an increased risk of cognitive dysfunction and dementia. The increased risk of dementia concerns both Alzheimer's disease and vascular dementia. Although some uncertainty remains into the exact pathogenesis, several mechanisms through which DM2 may affect the brain have now been identified. First, factors related to the 'metabolic syndrome', a cluster of metabolic and vascular risk factors (e.g. dyslipidaemia and hypertension) that is closely linked to DM2, may be involved. A number of these risk factors are predictors of cerebrovascular disease, accelerated cognitive decline and dementia. Secondly, hyperglycaemia may be involved, through adverse effects of potentially 'toxic' glucose metabolites on the brain and its vasculature. Thirdly, insulin itself may be involved. Insulin can directly modulate synaptic plasticity and learning and memory, and disturbances in insulin signalling pathways in the periphery and in the brain have recently been implicated in Alzheimer's disease and brain aging. Insulin also regulates the metabolism of beta-amyloid and tau, the building blocks of amyloid plaques and neurofibrillary tangles, the neuropathological hallmarks of Alzheimer's disease. In this paper, the evidence for the association between DM2 and dementia and for each of these underlying mechanisms will be reviewed, with emphasis on the role of insulin itself.

Alzheimer Disease↗
PubMed2005

Diabetes mellitus concomitantly facilitates the induction of long-term depression and inhibits that of long-term potentiation in hippocampus.

Memory impairments, which occur regularly across species as a result of ageing, disease (such as diabetes mellitus) and psychological insults, constitute a useful area for investigating the neurobiological basis of learning and memory. Previous studies in rats found that induction of diabetes (with streptozotocin, STZ) impairs long-term potentiation (LTP) but enhances long-term depression (LTD) induced by high- (HFS) and low-frequency stimulations (LFS), respectively. Using a pairing protocol under whole-cell recording conditions to induce synaptic plasticity at Schaffer collateral synapses in hippocampal CA1 slices, we show that LTD and LTP have similar magnitudes in diabetic and age-matched control rats. But, in diabetic animals, LTD is induced at more polarized and LTP more depolarized membrane potentials (V(ms)) compared with controls: diabetes produces a 10 mV leftward shift in the threshold for LTD induction and 10 mV rightward shift in the LTD-LTP crossover point of the voltage-response curve for synaptic plasticity. Prior repeated short-term potentiations or LTP are known to similarly, though reversibly, lower the threshold for LTD induction and raise that for LTP induction. Thus, diabetes- and activity-dependent modulation of synaptic plasticity (referred to as metaplasticity) display similar phenomenologies. In addition, compared with naïve synapses, prior induction of LTP produces a 10 mV leftward shift in Vms for inducing subsequent LTD in control but not in diabetic rats. This could indicate that diabetes acts on synaptic plasticity through mechanisms involved in metaplasticity. Persistent facilitation of LTD and inhibition of LTP may contribute to learning and memory impairments associated with diabetes mellitus.

Animals↗
PubMed2003

[Diabetic encephalopathy: an underexposed complication of diabetes mellitus].

Diabetes mellitus seems to be associated with gradually developing end-organ damage to the central nervous system. This relatively unknown complication of both diabetes type 1 and type 2 can be referred to as 'diabetic encephalopathy'. Measurable manifestations are electrophysiological and structural changes and limitations in the cognitive functioning. The mechanisms responsible for this diabetic encephalopathy are only partially known. Chronic metabolic and vascular changes seem to play an important role. The effects of diabetes on the brain are most distinct in the elderly. This may be the consequence of interactions between the mechanisms that underlie the ageing of the brain, dementia and the origin of diabetic complications. At present there are few leads for the targeted diagnostics and treatment of individual patients.

Aging↗
PubMed2003

Increased spike broadening and slow afterhyperpolarization in CA1 pyramidal cells of streptozotocin-induced diabetic rats.

Diabetes mellitus is associated with impairments of cognitive function both in humans and animal models. In diabetic rats cognitive deficits are related to alterations in activity-dependent synaptic plasticity in the hippocampus. Many similarities with the pathophysiology of normal brain aging have been noted, and the view emerges that the effects of diabetes on the brain are best described as "accelerated brain aging."In the present study we examined whether CA1 pyramidal neurons from streptozotocin-induced diabetic rats display an increased slow afterhyperpolarization, often considered as a hallmark of neuronal aging. We found no differences in resting membrane potential, input resistance, membrane time-constant, and action potential amplitude and duration between CA1 pyramidal neurons from streptozotocin-induced diabetic and age-matched control rats. During a train of action potentials, however, there is an increased broadening of the action potentials in diabetic animals, so-called "spike broadening." The amplitude of the slow afterhyperpolarization elicited by a train of action potentials is indeed increased in diabetic animals. Interestingly, when the slow afterhyperpolarization is elicited by a Ca(2+) spike, there is no difference between control and diabetic rats. This indicates that the increased slow afterhyperpolarization in diabetes is likely to be due to an increased Ca(2+) influx resulting from the increased spike broadening. These data underscore the notion that the diabetic brain at the neuronal level shares properties with brain aging.

Action Potentials↗
PubMed2003

Insulin inhibits extracellular regulated kinase 1/2 phosphorylation in a phosphatidylinositol 3-kinase (PI3) kinase-dependent manner in Neuro2a cells.

Insulin signalling is well studied in peripheral tissue, but not in neuronal tissue. To gain more insight into neuronal insulin signalling we examined protein kinase B (PKB) and extracellular regulated kinase 1 and 2 (ERK1/2) regulation in serum-deprived Neuro2a cells. Insulin phosphorylated PKB in a dose-dependent manner but reduced phosphorylation of ERK1/2. Both processes were phosphatidylinositol 3-kinase (PI3K) dependent. Interestingly, blockade of PI3K in combination with insulin induced phosphorylation of ERK1/2. The phosphorylation of ERK1/2 could be blocked with a specific inhibitor of mitogen-activated protein/ERK kinase (MEK), suggesting that it was mediated through the highly conserved Ras-Raf-MEK-ERK1/2 pathway. Prolonged exposure to high concentrations of insulin resulted in a desensitized PI3K-PKB route. The insulin-induced inhibition of ERK1/2 phosphorylation was also diminished when the PI3K-PKB route was desensitized. Blockade of PI3K in combination with insulin, however, still resulted in an unaltered MEK-dependent phosphorylation of ERK1/2. We conclude that PI3K is an important integrator of insulin signalling in Neuro2a cells as it regulates activation of PKB and inhibition of ERK1/2, and is sensitive to the duration of the insulin stimulus.

Animals↗
PubMed2002

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 alphaCaMKII 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.

Animals↗
PubMed2001

Learning and memory in streptozotocin-induced diabetic rats in a novel spatial/object discrimination task.

Diabetes mellitus is associated with disturbances of cognitive functioning. The aim of this study was to examine cognitive functioning in diabetic rats using the 'Can test', a novel spatial/object learning and memory task, without the use of aversive stimuli. Rats were trained to select a single rewarded can from seven cans. Mild water deprivation provided the motivation to obtain the reward (0.3 ml of water). After 5 days of baseline training, in which the rewarded can was marked by its surface and position in an open field, the animals were divided into two groups. Diabetes was induced in one group, by an intravenous injection of streptozotocin. Retention of baseline training was tested at 2-weekly intervals for 10 weeks. Next, two adapted versions of the task were used, with 4 days of training in each version. The rewarded can was a soft-drink can with coloured print. In a 'simple visual task' the soft-drink can was placed among six white cans, whereas in a 'complex visual task' it was placed among six soft-drink cans from different brands with distinct prints. In diabetic rats the number of correct responses was lower and number of reference and working memory errors higher than in controls in the various versions of the test. Switches between tasks and increases in task complexity accentuated the performance deficits, which may reflect an inability of diabetic rats to adapt behavioural strategies to the demands of the tasks.

Animals↗
PubMed2001

The effect of gamma-linolenic acid-alpha-lipoic acid on functional deficits in the peripheral and central nervous system of streptozotocin-diabetic rats.

Diabetes mellitus can lead to functional and structural deficits in both the peripheral and central nervous system. The pathogenesis of these deficits is multifactorial, probably involving, among others, microvascular dysfunction and oxidative stress. The present study examined the effects of 12 weeks of treatment with a conjugate of the essential fatty acid gamma-linolenic acid and the anti-oxidant alpha-lipoic acid (GLA-LA) on functional deficits in the peripheral and central nervous system in streptozotocin-diabetic rats. Treatment was initiated 16 weeks after diabetes induction. Sciatic nerve motor and sensory conduction velocity, brainstem auditory evoked potentials and visual evoked potentials were measured in control, untreated and GLA-LA treated diabetic rats. Also, long-term potentiation, a form of synaptic plasticity used as a model for learning and memory at the cellular level, was examined in hippocampal slices. GLA-LA treatment (50 mg/kg/day) did not reverse established deficits in nerve conduction velocity or in evoked potential latencies in diabetic rats. However, GLA-LA treatment did improve long-term potentiation in the hippocampus. It is concluded that GLA-LA, which is known to improve early deficits in peripheral nerve conduction in diabetic rats, is unable to reverse late deficits. However, the compound does reverse established deficits in long-term potentiation, suggesting that at least part of its activity is specifically directed at synaptic plasticity.

Animals↗
PubMed2001

Cerebral metabolism in streptozotocin-diabetic rats: an in vivo magnetic resonance spectroscopy study.

AIMS/HYPOTHESIS: It is increasingly evident that the brain is another site of diabetic end-organ damage. The pathogenesis has not been fully explained, but seems to involve an interplay between aberrant glucose metabolism and vascular changes. Vascular changes, such as deficits in cerebral blood flow, could compromise cerebral energy metabolism. We therefore examined cerebral metabolism in streptozotocin-diabetic rats in vivo by means of localised 31P and 1H magnetic resonance spectroscopy. METHODS: Rats were examined 2 weeks and 4 and 8 months after diabetes induction. A non-diabetic group was examined at baseline and after 8 months. RESULTS: In 31P spectra the phosphocreatine:ATP, phosphocreatine:inorganic phosphate and ATP:inorganic phosphate ratios and intracellular pH in diabetic rats were similar to controls at all time points. In 1H spectra a lactate resonance was detected as frequently in controls as in diabetic rats. Compared with baseline and 8-month controls 1H spectra did, however, show a statistically significant decrease in N-acetylaspartate:total creatine (-14% and -23%) and N-acetylaspartate:choline (-21% and -17%) ratios after 2 weeks and 8 months of diabetes, respectively. CONCLUSION/INTERPRETATION: No statistically significant alterations in cerebral energy metabolism were observed after up to 8 months of streptozotocin-diabetes. These findings indicate that cerebral blood flow disturbances in diabetic rats do not compromise the energy status of the brain to a level detectable by magnetic resonance spectroscopy. Reductions in N-acetylaspartate levels in the brain of STZ-diabetic rats were shown by 1H spectroscopy, which could present a marker for early metabolic or functional abnormalities in cerebral neurones in diabetes.

Adenosine Triphosphate↗