(Pre)diabetes, brain aging, and cognition

Abstract

Cognitive dysfunction and dementia have recently been proven to be common (and underrecognized) complications of diabetes mellitus (DM). In fact, several studies have evidenced that phenotypes associated with obesity and/or alterations on insulin homeostasis are at increased risk for developing cognitive decline and dementia, including not only vascular dementia, but also Alzheimer's disease (AD). These phenotypes include prediabetes, diabetes, and the metabolic syndrome. Both types 1 and 2 diabetes are also important risk factors for decreased performance in several neuropsychological functions. Chronic hyperglycemia and hyperinsulinemia primarily stimulates the formation of Advanced Glucose Endproducts (AGEs), which leads to an overproduction of Reactive Oxygen Species (ROS). Protein glycation and increased oxidative stress are the two main mechanisms involved in biological aging, both being also probably related to the etiopathogeny of AD. AD patients were found to have lower than normal cerebrospinal fluid levels of insulin. Besides its traditional glucoregulatory importance, insulin has significant neurothrophic properties in the brain. How can clinical hyperinsulinism be a risk factor for AD whereas lab experiments evidence insulin to be an important neurothrophic factor? These two apparent paradoxal findings may be reconciliated by evoking the concept of insulin resistance. Whereas insulin is clearly neurothrophic at moderate concentrations, too much insulin in the brain may be associated with reduced amyloid-beta (Abeta) clearance due to competition for their common and main depurative mechanism - the Insulin-Degrading Enzyme (IDE). Since IDE is much more selective for insulin than for Abeta, brain hyperinsulinism may deprive Abeta of its main clearance mechanism. Hyperglycemia and hyperinsulinemia seems to accelerate brain aging also by inducing tau hyperphosphorylation and amyloid oligomerization, as well as by leading to widespread brain microangiopathy. In fact, diabetes subjects are more prone to develop extense and earlier-than-usual leukoaraiosis (White Matter High-Intensity Lesions - WMHL). WMHL are usually present at different degrees in brain scans of elderly people. People with more advanced WMHL are at increased risk for executive dysfunction, cognitive impairment and dementia. Clinical phenotypes associated with insulin resistance possibly represent true clinical models for brain and systemic aging.

Is Insulin Resistant Brain State a Central Feature of the Metabolic-Cognitive Syndrome?

“…In type 1 diabetes mellitus (T1DM), only a mild decrease of speed of information processing and psychomotor efficiency has been shown in nondemented subjects [31], while inT2DM, memory and executive functions have been found to be impaired [32]. One clue as to why T1DM and T2DM may differ in the progression of cognitive impairment is a potential interaction between diabetes and age [33]. In fact, T2DM is more prevalent with increasing age, and clinically relevant decreases in cognitive function are more likely to occur in elderly T2DM patients [34].…”

“…In fact, T2DM is more prevalent with increasing age, and clinically relevant decreases in cognitive function are more likely to occur in elderly T2DM patients [34]. Another possible explanation for the differential effects on cognitive function is insulin resistance, a feature more prevalent in T2DM than in T1DM [33].…”

“…In addition, they regulate growth, survival, and myelin production/maintenance in oligodendrocytes [39]. On the other hand, hyperglycemia, diabetes mellitus, and insulin resistance increased the risk of developing cerebrovascular disease, microand macrovascular complications of varying severity [33], as well as increased carotid intima-media thickness [40][41][42], or greater grade of infarcted areas during a cerebrovascular event [43]. Increased concentrations of anti-fibrinolytic and other procoagulant factors have been found in diabetes mellitus as well as alterations in nitric oxide metabolism.…”

The Diabetic Brain and Dementia

“…but more cerebrovascular lesions including microvascular lesions and white matter changes than subjects without DM [5, [21][22][23][24][25][26][27]. Vasculo-neural dysfunction has been suggested to represent a potential etiological linkage between DMT2 and AD [6,28], while others suggested that the association between DM and dementia is only partially mediated through cerebrovascular disease and that DM is associated independently with overal dementia among elderly, but not with AD or vascular dementia [29].…”

Untitled

“…Converging environmental and genetic risk factors trigger a pathophysiologic cascade, over decades, leads to Alzheimer pathology and dementia. [5] …”