Microvascular Disease in Type 1 Diabetes Alters Brain Activation

Wessels, Alette M.; Rombouts, Serge A.R.B.; Şimşek, Suat; Kuijer, Joost P.A.; Kostense, Piet J.; Barkhof, Frederik; Scheltens, Philip; Snoek, Frank J.; Heine, Robert J.

doi:10.2337/diabetes.55.02.06.db05-0680

Cited by 65 publications

(48 citation statements)

References 47 publications

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“…Moreover, retinopathy and peripheral neuropathy in type 1 diabetes patients have been shown to be predictive of DACD (19,20). We have shown that type 1 diabetes patients with proliferative retinopathy showed a different cerebral activation pattern, using functional MRI, than those without retinopathy to a cognitive test (21). Reske-Nielsen et al described, more than 30 years ago in autopsy studies, the changes in the cerebral microvasculature derived from diabetes patients (22).…”

Section: Controls Nz13mentioning

confidence: 62%

Increased Nε-(carboxymethyl)-lysine levels in cerebral blood vessels of diabetic patients and in a (streptozotocin-treated) rat model of diabetes mellitus

Deutekom

Niessen²,

Schalkwijk³

et al. 2008

European Journal of Endocrinology

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Objective: Non-enzymatic glycation of proteins and their end products (advanced glycation end products, AGE) have been implicated in the pathogenesis of diabetic complications. Our aim was to evaluate the association between diabetes mellitus (DM) and the accumulation of one of the most abundant AGEs, N3-(carboxymethyl)-lysine (CML), in cerebral vessels. Research design and methods: Brain tissue samples were obtained by autopsy from 20 DM patients and 13 age-matched controls. In addition, we investigated brain tissue samples of seven rats after induction of diabetes with streptozotocin (STZ) and six non-diabetic control rats. We used an immunohistochemical staining method to examine the CML immunoreactivity in the cerebral vessels. Results: Staining intensity of CML was significantly higher in cerebral vessels of diabetic patients than in non-diabetic subjects (median of the immunohistochemical intensity score/cm 2 in the diabetic group of 0.85 (interquartile range (IQR) 0.66-1.52) vs 0.63 in the control group (IQR 0.44-0.70); PZ0.002). Furthermore, there was a similar significant difference in CML staining intensity of cerebral vessels between STZ diabetic rats and non-diabetic control rats (median of the immunohistochemical intensity score/cm 2 in the diabetic group of 1.08 (IQR 0.73-1.43) vs 0.23 in the control group (IQR 0.12-0.43); PZ0.003). Conclusions: Accumulation of CML-modified proteins is significantly greater in the cerebral vessels of the diabetic patients than their age-matched controls. This association has been confirmed in the insulin-deficient diabetic rat model. It may be possible that the excessive accumulation of AGE-modified proteins in the cerebral vasculature alters the local environment and microcirculation and thereby contributes to the development of cognitive impairments in diabetes. Therefore, additional study on the causal link between AGE accumulation and cognitive dysfunction and the potential benefits of AGEblocking and/or breaking compounds is indicated.European Journal of Endocrinology 158 655-660

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Section: Controls Nz13mentioning

confidence: 62%

Increased Nε-(carboxymethyl)-lysine levels in cerebral blood vessels of diabetic patients and in a (streptozotocin-treated) rat model of diabetes mellitus

Deutekom

Niessen²,

Schalkwijk³

et al. 2008

European Journal of Endocrinology

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“…Structural changes of this sort ought to affect brain function as well, and in a separate report that included many of the same subjects, Wessels' group was able to demonstrate the existence of differences in brain activation during a cognitively demanding working memory task [20]. Normally, a deactivation of certain brain regions occurs during working memory, and this can be measured using functional MRI techniques.…”

Section: Cortical Atrophy Cerebral Hypoperfusion and Diabetic Prolifmentioning

confidence: 99%

Diabetes and brain damage: more (or less) than meets the eye?

Ryan

2006

Diabetologia

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Brain damage is now a well-established complication of diabetes, but its pathophysiological basis remains controversial. Until very recently, most research on this topic was devoted to demonstrating that hypoglycaemic events are the primary cause of neurocognitive dysfunction. This was a plausible hypothesis because the central nervous system (CNS) has very limited stores of glucose and other substrates, but neurons have a very high rate of glucose utilisation; any reduction in glucose availability would probably induce neuroglycopenia, ultimately leading to significant neuronal damage. Support for this view came from research demonstrating that profound hypoglycaemia could produce neuronal necrosis [1] and induce distinctive patterns of neuropathological [2] and neurocognitive [3] impairment in humans who had experienced very low blood glucose levels over an extended period of time. Fortunately, most diabetic patients never experience profound hypoglycaemia. Although some writers have speculated that recurrent episodes of moderately severe hypoglycaemia could induce a less severe degree of neurocognitive dysfunction [4,5], most recent studies of children [6] and adults [7,8] have failed to find compelling evidence for that possibility. Taken together, these findings suggest that there is not a linear relationship between falling blood glucose levels and permanent brain dysfunction. Rather, necrotising neuronal damage occurs only after the threshold for cerebral energy failure is reached-most typically when blood glucose values fall below 1.5 mmol, and the electroencephalogram has reached an isoelectric (flat) state [9]. Retinopathy predicts neurocognitive dysfunctionIf moderately low blood glucose levels are not sufficient to induce detectable brain damage, and if profound hypoglycaemia is a rare event, to what can we attribute the modest, but consistently reported, brain dysfunction found in many diabetic patients? A growing literature now suggests that functional and structural CNS changes may have a vascular basis, and reflect the occurrence of cerebral microangiopathy that is secondary to chronic hyperglycaemia and indicated by the presence of retinopathy. For example, when adults with type 1 diabetes were followed for 7 years, a significant decline in mental efficiency was found over time, but this was limited to those who either had clinically significant diabetic proliferative retinopathy when they entered the study or who subsequently developed diabetic proliferative retinopathy during the follow-up period; those without retinopathy showed no cognitive changes. The magnitude of cognitive decline was further, and independently, influenced by elevated systolic blood pressure and by duration of diabetes [10]. The presence of retinopathy-even relatively early retinopathy-has also been associated with cerebral white matter lesions [11] in otherwise healthy diabetic adults, and a recent exploratory analysis has suggested that increasing severity of retinopathy is related to reductions in cortical grey matter ...

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“…4,5 A correlation was reported between some of these structural changes and the onset age of DM, levels of HbA1c, history of hypoglycaemia attack and the presence of retinopathy. [6][7][8] Some investigators detected hyperintense lesions in the white matter, increased cerebrospinal fluid volume, global cerebral atrophy, stable hippocampus and amygdala volume and decreased cerebral gray matter density in patients with Type 1 DM on MRI. 6,[8][9][10] Neurocognitive disorders are also lesser known complications of Type 1 DM.…”

Section: Introductionmentioning

confidence: 99%