Discovering the Glymphatic Factor in the Epilepsy-Neurodegeneration Duo through Synergy of Basic and Clinical Research
Progetto Clinical or subclinical seizures are increasingly reported in the most common neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease (AD, PD) and Lewy body dementia (LBD). Although largely ignored in the past, epileptiform activity appears to aggravate cognitive decline and predicts a poor prognosis. The lack of mechanistic data hampers early diagnosis and effective
interventions, to prevent the detrimental effects of seizures. This multidisciplinary team will investigate the relationship between epileptiform activity and neurodegenerative process, through a synergy of preclinical and clinical studies using neurobiological
(biomarkers and multi-omics), neuroimaging (neuropathological burden, connectome analysis, neurodegeneration), neurophysiological (brain dynamics, patch-clamp), and neurobehavioral experiments. It will test the original hypothesis if the ageingrelated
deficit in the glymphatic clearance of the brain from misfolded α-synuclein, amyloid-β, tau and other interstitial solutes associated with the neurodegenerative process could trigger epileptiform activity by overwhelming the homeostatic mechanism of
the brain. It will also verify the role of “anti-epileptic” reserves of the nervous system and environmental factors (inhibition, functional connectivity from frontal to limbic regions, lifestyle, habits, sleep, medications, and cognitive surplus) in determining the prevalence
of epileptiform activity with cognitive decline. The outcome of these studies will unravel brain circuits and functional correlates of epileptiform activity in AD, PD, and LBD, as risk factors leading to seizures, with detrimental consequences. Established procedures,
mechanistic insights, and biomarkers for the epileptiform activity will provide critical insights into the biology of neurodegenerative disease and substantiate the latest recommendations of the European Societies of Clinical Neurosciences, through dissemination and clinical use.