Monitoring synaptic pathology in Alzheimer's disease through fluid and PET imaging biomarkers: a comprehensive review and future perspectives.

Nicola B Mercuri, Enzo Emanuele, Audrey Gabelle, Simone Lista, Susana López-Ortiz, Juan Martín-Hernández, Bruno P Imbimbo, Filippo Caraci, Robert Nisticò, Henrik Zetterberg, Alejandro Santos-Lozano, Nunzia Maisto, Camillo Imbimbo

Journal: Molecular psychiatry 2024;29(3):847-857

PMID: 38228892

Full Text on Nature Publishing Group View on PubMed

Abstract

Alzheimer's disease (AD) is currently constrained by limited clinical treatment options. The initial pathophysiological event, which can be traced back to decades before the clinical symptoms become apparent, involves the excessive accumulation of amyloid-beta (Aβ), a peptide comprised of 40-42 amino acids, in extraneuronal plaques within the brain. Biochemical and histological studies have shown that overaccumulation of Aβ instigates an aberrant escalation in the phosphorylation and secretion of tau, a microtubule-binding axonal protein. The accumulation of hyperphosphorylated tau into intraneuronal neurofibrillary tangles is in turn correlated with microglial dysfunction and reactive astrocytosis, culminating in synaptic dysfunction and neurodegeneration. As neurodegeneration progresses, it gives rise to mild clinical symptoms of AD, which may eventually evolve into overt dementia. Synaptic loss in AD may develop even before tau alteration and in response to possible elevations in soluble oligomeric forms of Aβ associated with early AD. These findings largely rely on post-mortem autopsy examinations, which typically involve a limited number of patients. Over the past decade, a range of fluid biomarkers such as neurogranin, α-synuclein, visinin-like protein 1 (VILIP-1), neuronal pentraxin 2, and β-synuclein, along with positron emission tomography (PET) markers like synaptic vesicle glycoprotein 2A, have been developed. These advancements have facilitated the exploration of how synaptic markers in AD patients correlate with cognitive impairment. However, fluid biomarkers indicating synaptic loss have only been validated in cerebrospinal fluid (CSF), not in plasma, with the exception of VILIP-1. The most promising PET radiotracer, [C]UCB-J, currently faces significant challenges hindering its widespread clinical use, primarily due to the necessity of a cyclotron. As such, additional research geared toward the exploration of synaptic pathology biomarkers is crucial. This will not only enable their extensive clinical application, but also refine the optimization process of AD pharmacological trials.

Address: i+HeALTH Strategic Research Group, Department of Health Sciences, Miguel de Cervantes European University (UEMC), 47012, Valladolid, Spain. [email protected].; i+HeALTH Strategic Research Group, Department of Health Sciences, Miguel de Cervantes European University (UEMC), 47012, Valladolid, Spain.; Physical Activity and Health Research Group (PaHerg), Research Institute of the Hospital 12 de Octubre ('imas12'), 28041, Madrid, Spain.; 2E Science, 27038, Robbio, Italy.; Experimental Neurology Laboratory, IRCCS Santa Lucia Foundation, 00143, Rome, Italy.; Department of Systems Medicine, University of Rome Tor Vergata, 00133, Rome, Italy.; CMRR, Memory Resources and Research Center, Montpellier University of Excellence i-site, 34295, Montpellier, France.; i+HeALTH Strategic Research Group, Department of Health Sciences, Miguel de Cervantes European University (UEMC), 47012, Valladolid, Spain.; Laboratory of Pharmacology of Synaptic Plasticity, EBRI Rita Levi-Montalcini Foundation, 00143, Rome, Italy.; Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, 00185, Rome, Italy.; Department of Brain and Behavioral Sciences, University of Pavia, 27100, Pavia, Italy.; Department of Drug and Health Sciences, University of Catania, 95125, Catania, Italy.; Neuropharmacology and Translational Neurosciences Research Unit, Oasi Research Institute-IRCCS, 94018, Troina, Italy.; Department of Research and Development, Chiesi Farmaceutici, 43122, Parma, Italy.; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, 431 80, Mölndal, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 431 80, Mölndal, Sweden.; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, WC1N, London, UK.; UK Dementia Research Institute at UCL, WC1E 6BT, London, UK.; Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.; Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, 53726, WI, USA.; Laboratory of Pharmacology of Synaptic Plasticity, EBRI Rita Levi-Montalcini Foundation, 00143, Rome, Italy. [email protected].; School of Pharmacy, University of Rome "Tor Vergata", 00133, Rome, Italy. [email protected].

DOI: 10.1038/s41380-023-02376-6

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https://doi.org/10.1038/s41380-023-02376-6

MeSH Terms: Humans, alpha-Synuclein, Alzheimer Disease, Amyloid beta-Peptides, Biomarkers, Brain, C-Reactive Protein, Nerve Tissue Proteins, Neurocalcin, Neurofibrillary Tangles, Neurogranin, Positron-Emission Tomography, Synapses, tau Proteins