Abstract
Dementia, a condition that frequently afflicts patients in advanced stages of Parkinson's disease (PD), results in decreased quality of life and survival time. Nevertheless, the pathological mechanisms underlying Parkinson's disease dementia (PDD) are not completely understood. The symptoms characteristic of PDD may be the result of functional and structural deficiencies. The present study implicates the accumulation of Lewy bodies in the cortex and limbic system as a potent trigger in the development of PDD. In addition, significant Alzheimer-type pathologies, including amyloid-β (Aβ) plaques and NFTs, are observed in almost half of PDD patients. Interestingly, links between PDD pathogenesis and the mechanisms underlying the development of insulin resistance have begun to emerge. Furthermore, previous studies have demonstrated that insulin treatment reduces amyloid plaques in Alzheimer's disease (AD), and normalizes the production and functionality of dopamine and ameliorates motor impairments in 6-OHDA-induced rat PD models. GSK3β, a downstream substrate of PI3K/Akt signaling following induction by insulin and IGF-1, exerts an influence on AD and PD physiopathology. The genetic overexpression of GSK3β in cortex and hippocampus results in signs of neurodegeneration and spatial learning deficits in in vivo models (Lucas et al., 2001), whereas its inhibition results in improvements in cognitive impairment in these rodents, including AD and PD. Accordingly, insulin- or IGF-1-activated PI3K/Akt/GSK3β signaling may be involved in PDD pathogenesis, at least in the pathology of PD-type + AD-type.
Highlights
Parkinson’s disease (PD), a major neurodegenerative disorder, is caused by dopaminergic neuronal loss in the substantia nigra as well as the formation of intracellular inclusion bodies, known as Lewy bodies
One of the most important recent findings is the link between Parkinson’s disease dementia (PDD) pathogenesis and the mechanisms underlying the development of insulin resistance; studies have found that patients with PDD are prone to comorbid insulin resistance (Bosco et al, 2012; Ashraghi et al, 2016), even when they were unaffected by Diabetes Mellitus
This review provides a summary of the data suggesting that insulin/insulin-like growth factor-1 (IGF-1) signaling and its downstream phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK-3β) cascades may be associated with the pathological processes of PDD
Summary
Parkinson’s disease (PD), a major neurodegenerative disorder, is caused by dopaminergic neuronal loss in the substantia nigra as well as the formation of intracellular inclusion bodies, known as Lewy bodies. In addition to the classic motor dysfunction symptoms of PD, non-movement disorders involving cognitive deficits and dementia are increasingly acknowledged as core symptoms of PD. Parkinson’s disease dementia (PDD) has been reported across the entire course of PD but is prevalent in advanced stages, resulting in high morbidity and mortality in approximately 80–90% by the age of 90 (Gratwicke et al, 2015)
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