Mild cognitive impairment (MCI) is an intermediate stage between normal and pathological brain aging, with 30% to 50% progressing to dementia within 3 to 5 years. Early identification of individuals a Show more
Mild cognitive impairment (MCI) is an intermediate stage between normal and pathological brain aging, with 30% to 50% progressing to dementia within 3 to 5 years. Early identification of individuals at high risk of progression is crucial for public health strategies. The INTERCEPTOR project included 398 MCI individuals. Baseline assessment included harmonized procedures for sociodemographic, clinical, neuropsychological, genetic (apolipoprotein E), cerebrospinal fluid (amyloid beta tau), electroencephalogram (brain connectivity), magnetic resonance imaging (hippocampal volumetry), and fluorodeoxyglucose positron emission tomography. The baseline and follow-up were completed by 351 individuals with MCI with neuropsychological tests every 6 months for 3 years. Dementia developed in 104 individuals (29.6%), including 85 (22.4%) who met core clinical criteria for probable and possible Alzheimer's disease dementia. A Cox model combining clinical and sociodemographic data achieved a concordance index of 72%, which increased to 82% when neuropsychology and biomarkers were added. The INTERCEPTOR nomogram represents a tool for predicting dementia progression risk, supporting public health strategies, including screening for risk assessment and risk/benefit ratio in innovative treatments. Show less
The endoplasmic reticulum stress and the unfolded protein response are triggered following an imbalance between protein load and protein folding. Until recently, two possible outcomes of the unfolded Show more
The endoplasmic reticulum stress and the unfolded protein response are triggered following an imbalance between protein load and protein folding. Until recently, two possible outcomes of the unfolded protein response have been considered: life or death. We sought to substantiate a third alternative, dedifferentiation, mesenchymal shift, and activation of the antioxidant response by using typical endocrine cells, i.e. thyroid cells. The thyroid is a unique system both of endoplasmic reticulum stress (a single protein, thyroglobulin represents the majority of proteins synthesized in the endoplasmic reticulum by the thyrocyte) and of polarized epithelium (the single layer of thyrocytes delimiting the follicle). Following endoplasmic reticulum stress, in thyroid cells the folding of thyroglobulin was disrupted. The mRNAs of unfolded protein response were induced or spliced (X-box binding protein-1). Differentiation was inhibited: mRNA levels of thyroid specific genes, and of thyroid transcription factors were dramatically downregulated, at least in part, transcriptionally. The dedifferentiating response was accompanied by an upregulation of mRNAs of antioxidant genes. Moreover, cadherin-1, and the thyroid (and kidney)-specific cadherin-16 mRNAs were downregulated, vimentin, and SNAI1 mRNAs were upregulated. In addition, loss of cortical actin and stress fibers formation were observed. Together, these data indicate that ER stress in thyroid cells induces dedifferentiation, loss of epithelial organization, shift towards a mesenchymal phenotype, and activation of the antioxidant response, highlighting, at the same time, a new and wide strategy to achieve survival following ER stress, and, as a sort of the other side of the coin, a possible new molecular mechanism of decline/loss of function leading to a deficit of thyroid hormones formation. Show less