Biology subjects

Delli Pizzi, S.

Publications and source records attributed to Delli Pizzi, S..

5 recordsLinked to original sources

bioRxiv2026

Analysis of the off-target interaction of amyloid PET tracers with human brain sulfotransferases

Positron emission tomography (PET) tracers targeting amyloid-{beta} (A{beta}) are central to the diagnosis and staging of Alzheimer's disease (AD). However, growing evidence indicates that these tracers can engage off-target molecules, complicating signal interpretation. Sulfotransferases (SULTs) have been experimentally identified as binding partners of 11C-Pittsburgh Compound-B (PiB). However, whether the clinically used fluorinated PiB derivatives flutemetamol and flutafuranol interact with brain-expressed SULTs is yet unexplored. Here, we combined multi-omic transcriptomic profiling with molecular docking and molecular dynamics (MD) simulations to assess the structural interactions of SULT-tracer complexes. Analysis of the Genotype-Tissue Expression project and the Human Protein Atlas identified SULT1A1, SULT1A3, and SULT4A1 as the SULT isoforms predominantly expressed in the human brain. Docking and MD simulations showed that all three tracers form energetically comparable complexes within the catalytic pockets of these isoforms, yet their dynamic stability varied in an enzyme- and tracer-specific manner. PiB and flutemetamol were stably accommodated in SULT1A1, but PiB lost its initial pose in SULT4A1. Flutafuranol showed weaker binding in SULT1A1, yet formed stable complexes in SULT1A3 and SULT4A1. Notably, SULT1A1, SULT1A3, and SULT4A1 are all expressed in the cerebellum, the brain region used as a reference for A{beta} PET signal normalization. These findings provide a structural framework for off-target tracer interaction with brain SULTs and suggest that the intracellular enzymatic environment may contribute to variability in A{beta} PET signals beyond fibrillar A{beta} deposition.

neuroscience↗

bioRxiv2026

A Shared Entropic Axis Spans States of Consciousness Across Pharmacological and Clinical Conditions

A general account of how diverse states of consciousness arise from brain activity requires a quantitative framework that generalises across them. The Entropic Brain Theory proposes that states of consciousness can be ordered along a single dimension defined by the entropy of spontaneous neural activity, but this prediction has not been tested across pharmacological and clinical perturbations within a common analytical pipeline. Here we quantify the temporal irregularity of time-resolved small-world topology using sample entropy, applying the same pipeline to pharmacological (psychedelics, modafinil, propofol anaesthesia) and clinical (schizophrenia) fMRI datasets. Propofol anaesthesia occupied the low-entropy end of the axis; psychedelic states and schizophrenia occupied the high end. The ordering tracks combined modulations of the level and content of consciousness, ranging from reduced awareness under anaesthesia to the heightened arousal and expanded experience of psychedelic states and the disorganised, dysregulated processing of schizophrenia. Crucially, this result was not reducible to fluctuations in mean functional connectivity, and was supported by convergent reorganisation of higher-order association cortex under psychedelics and anaesthesia, alongside a distributed loss of network specificity in schizophrenia. These findings provide cross-condition empirical support for an entropic continuum of brain states and identify the temporal diversity of large-scale network reconfiguration as a primary axis of conscious dynamics.

neuroscience↗

bioRxiv2025

Off-target interaction of the amyloid PET imaging tracer PiB with acetylcholinesterase

Pittsburgh compound B (PiB) is a widely used Positron Emission Tomography (PET) tracer for detecting amyloid-{beta} (A{beta}) deposits in Alzheimers disease (AD). While PiB is assumed to bind selectively to A{beta}, emerging evidence suggests off-target interactions that may complicate PET signal interpretation. Here, we report that PiB can interact with acetylcholinesterase (AchE), a key enzyme in the cholinergic system. Similarity screening identified the AchE ligand thioflavin T (ThT) as the top structural analog of PiB. Docking studies and molecular dynamics simulations showed that PiB stably binds the peripheral anionic site (PAS) of AchE, with binding energies comparable to ThT and clinically relevant AchE inhibitors. In vitro fluorescence-based assays confirmed this interaction and suggest an involvement of the PAS. These findings indicate a stable off-target interaction between PiB and AChE with implications for interpreting PiB-PET signals in AD, particularly in regions with altered AchE expression or under AchE inhibitor therapy.

neuroscience↗

bioRxiv2018

Functional signature of conversion in Mild Cognitive Impairment patients

The entorhinal-hippocampal circuit is a strategic hub for memory but also the first site to be affected in the Alzheimers Disease (AD)-related pathology. We investigated MRI patterns of brain atrophy and functional connectivity in a study cohort obtained from the Alzheimers Disease Neuroimaging Initiative database including healthy control (HC), Mild Cognitive Impairment (MCI), and AD subjects. MCI individuals were clinically evaluated 24 months after the MRI scan, and the group further divided into a subset of subjects who either did (c-MCI) or did not (nc-MCI) convert to AD. Compared to HC subjects, AD patients exhibited a collapse of long-range connectivity from the hippocampus and entorhinal cortex, pronounced cortical/sub-cortical atrophy, and a dramatic decline in cognitive performances. c-MCI patients showed entorhinal and hippocampal hypo-connectivity, no signs of cortical thinning but evidence of right hippocampus atrophy. On the contrary, nc-MCI patients showed lack of brain atrophy, largely preserved cognitive functions, hippocampal and entorhinal hyper-connectivity with selected neocortical/sub-cortical regions mainly involved in memory processing and brain meta-stability. This hyper-connectivity can represent an early compensatory strategy to overcome the progression of cognitive impairment. This functional signature can also be employed for the diagnosis of c-MCI subjects.

neuroscience↗

bioRxiv2018

The pharmacological perturbation of brain zinc impairs BDNF-related signalling and the cognitive performances of young mice

Zinc (Zn2+) is a pleiotropic modulator of the neuronal and brain activity. The disruption of intraneuronal Zn2+ levels triggers neurotoxic processes and affects neuronal functioning. In this study, we investigated how the pharmacological modulation of brain Zn2+ affects synaptic plasticity and cognition in wild-type mice. To manipulate brain Zn2+ levels, we employed the Zn2+ (and copper) chelator 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ). CQ was administered for two weeks to 2.5-month-old (m.o.) mice, and effects studied on BDNF-related signalling, metalloproteinase activity as well as learning and memory performances. CQ treatment was found to negatively affect short- and long-term memory performances. The CQ-driven perturbation of brain Zn2+ was found to reduce levels of BDNF, synaptic plasticity-related proteins and dendritic spine density in vivo.\n\nOur study highlights the importance of choosing \"when\", \"where\", and \"how much\" in the modulation of brain Zn2+ levels. Our findings confirm the importance of targeting Zn2+ as a therapeutic approach against neurodegenerative conditions but, at the same time, underscore the potential drawbacks of reducing brain Zn2+ availability upon the early stages of development.

neuroscience↗