👤 Enrico Fontanella

We evaluated the accuracy of standard machine learning (ML) algorithms in predicting 1-year cognitive decline in Alzheimer's disease patients with mild cognitive impairment (ADMCI) using resting-state electroencephalographic (rsEEG) biomarkers enriched with APOE genotype, sex, age, and educational attainment data. The study analyzed datasets from 63 ADMCI patients obtained from an international archive. The ML algorithms included Simple Logistic Regression, Model Trees, Logistic Regression, K-nearest neighbor, and Support Vector Machine. Input features comprised lobar rsEEG source activities across delta (<4 Hz) to alpha (≈10-12 Hz) bands, cerebrospinal fluid (CSF Aβ1-42/p-tau), and structural magnetic resonance imaging (sMRI) biomarkers. Cognitive decline was assessed over a 1-year follow-up ("stable" vs. "decliner") based on Mini-Mental State Examination (MMSE) scores. The four independent ML algorithms accurately predicted changes in the MMSE score over a 1-year follow-up, with accuracies of 77-78% in ADMCI participants aged ≥ 70 years and 74-77% in those aged < 70 years. These findings suggest that rsEEG biomarkers in ADMCI patients may not only reveal underlying pathophysiological mechanisms affecting cortical arousal and vigilance but also hold predictive value for cognitive outcomes. Show less

Cell cycle and apoptosis regulator 2 (CCAR2, formerly known as DBC1) is a nuclear protein largely involved in DNA damage response, apoptosis, metabolism, chromatin structure and transcription regulation. Upon DNA lesions, CCAR2 is phosphorylated by the apical kinases ATM/ATR and this phosphorylation enhances CCAR2 binding to SIRT1, leading to SIRT1 inhibition, p53 acetylation and p53-dependent apoptosis. Recently, we found that also the checkpoint kinase Chk2 and the proteasome activator REGγ are required for efficient CCAR2-mediated inhibition of SIRT1 and induction of p53-dependent apoptosis.Here, we report that CCAR2 is required for the repair of heterochromatic DNA lesions, as cells knock-out for CCAR2 retain, at late time-points after genotoxic treatment, abnormal levels of DNA damage-associated nuclear foci, whose timely resolution is reinstated by HP1β depletion. Conversely, repair of DNA damages in euchromatin are not affected by CCAR2 absence.We also report that the impairment in heterochromatic DNA repair is caused by defective Chk2 activation, detectable in CCAR2 ablated cells, which finally impacts on the phosphorylation of the Chk2 substrate KAP1 that is required for the induction of heterochromatin relaxation and DNA repair.These studies further extend and confirm the role of CCAR2 in the DNA damage response and DNA repair and illustrate a new mechanism of Chk2 activity regulation. Moreover, the involvement of CCAR2 in the repair of heterochromatic DNA breaks suggests a new role for this protein in the maintenance of chromosomal stability, which is necessary to prevent cancer formation. Show less