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• W2034458421 abstract "Western countries are facing a pandemic of diabetes mellitus and metabolic syndrome, which mostly affect aging populations. Older individuals also have a higher prevalence of cognitive disorders. There is a lack of knowledge about what the main pathogenetic mechanisms of Alzheimer's disease (AD), the most frequent form of dementia, are and what the most relevant treatment targets are.1 AD was traditionally attributed to a primitive neurodegenerative etiology until observations that microvascular subcortical disease and cardiovascular risk factors are potent predictors of AD challenged this paradigm.2, 3 Small-vessel subcortical diseases such as leukoaraiosis and microbleeding are the direct consequence of chronic exposure to cardiometabolic risk factors. Evidence suggests that such small-vessel injury may represent the prime cause of AD, even decades before clinical dementia first appears.2, 3 How could a primarily subcortical injury start AD, which manifests particularly on the cortex? Neuroanatomical and functional brain imaging investigations have shown that deep subcortical areas are connected to specific cortical zones through axonal projections, maintaining cortex trophism and function. Deep areas in the brain experience chronic vascular damage, which disrupts such projections, as electrophysiological and neuroimaging investigations have documented. This stage is thought to precede the abnormal oligomeric amyloid deposition that is the traditional hallmark of AD.2, 3 Small-vessel impairment leads directly to amyloid overloading, because small vessels normally drain amyloid. The precapillary segment of the blood–brain barrier (BBB) in particular plays a pivotal role in regulating amyloid-β clearance; chronic degenerative changes at this level are reflected in the accumulation of amyloid within the brain.4 The abnormal amyloid oligomer deposition directly stimulates inflammation, as histochemistry investigations that have shown that proliferating glia surround amyloid plaques suggest.3 Inflammation over time is a further independent way that neuronal cells are lost, in part through triggering of apoptosis. Peripheral chronic micro-inflammation originates from adipose tissue in the majority of individuals with diabetes mellitus and metabolic syndrome. Peripheral inflammation cross-talks with its intracerebral counterpart. Peripheral proinflammatory cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor alpha affect the BBB. At this level, cytokines bind to specific endothelial receptors physiologically. Chronic elevation of such cytokines amplify intracerebral inflammatory pathways, mainly by stimulating glial cells.5, 6 The small-vessel degeneration dramatically increases BBB permeability to cytokines. Diabetes mellitus and metabolic syndrome are primarily insulin resistance conditions. Insulin crosses the BBB in a carrier-mediated process and then binds to specific tissue receptors. Several brain areas that AD specifically affects, such as the olfactory bulb, neocortex, hippocampus, and amygdala, are known to constitutionally express specific tyrosin kinase receptors for insulin. Well-documented effects of insulin on neuronal cells range from the regulation of neuronal glucose metabolism to the modulation of synaptic transmission to regulation of amyloid homeostasis. Peripheral hyperinsulinemia after insulin resistance decreases its intraneuronal effect because insulin receptors are downregulated. Several pieces of evidence indicating that low brain insulin signaling is associated with impaired learning and memory and with structural brain changes such as atrophy of the hippocampus and amygdala support the importance of brain insulin-resistance.7 Moreover, mice models of diabetes mellitus have demonstrated a greater frequency of the classical AD hallmarks such as tau hyperphosphorylation within tangles and neuronal cells loss, especially within the neocortex and hippocampus.7, 8 Moreover hyperinsulinemia can directly reduce amyloid degradation, because insulin and amyloid share the same degrading enzyme in the brain. It remains uncertain whether control of cardiovascular risk factors and inflammation may prevent or modify the course of AD. Although conventional antiinflammatory agents have not been effective in the treatment of clinical AD, future investigation may demonstrate the effectiveness of appropriately designed anti-inflammatory agents in early-stage AD. According to the insulin pathways hypothesis, the transnasal administration of insulin has been demonstrated to improve cognitive performance and brain metabolism in individuals with amnestic mild cognitive impairment and AD,8 but transnasal administration ceases to be effective after a few months. Finding the right way to intervene in brain insulin pathways is necessary. Subcortical small vessels may be the site of the earliest damage in AD, making it conceivable that intervening in cardiometabolic risk factors and inflammation may reduce AD incidence at a population level. A better understanding of the mechanisms underlying vascular damage would be a way to find effective treatment targets for AD. Moreover, building on the idea that cardiometabolic risk factors are the prime cause of subcortical small-vessel diseases, researchers should keep in mind that AD may not originate within the brain. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Giovanni Viscogliosi reviewed the current medical literature and wrote the letter. Vincenzo Marigliano reviewed the current medical literature and conceived of the letter. Sponsor's Role: None." @default.
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• W2034458421 date "2013-05-01" @default.
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• W2034458421 title "Alzheimer's Disease: How Far Have We Progressed? Lessons Learned from Diabetes Mellitus, Metabolic Syndrome, and Inflammation" @default.
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• W2034458421 doi "https://doi.org/10.1111/jgs.12242" @default.
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