Alzheimer’s disease (AD) is the most common cause of neurodegenerative dementia, whilst Parkinson’s disease (PD) is a neurodegenerative movement disorder. These two neurodegenerative disorders share the accumulation of toxic proteins as a pathological hallmark. The lack of definitive disease-modifying treatments for these neurogenerative diseases has led to the hypothesis of new pathogenic mechanisms to target and design new potential therapeutic approaches. The recent observation that the glymphatic system is supposed to be responsible for the movement of cerebrospinal fluid into the brain and clearance of metabolic waste has led to study its involvement in the pathogenesis of these classic proteinopathies. Aquaporin-4 (AQP4), a water channel located in the endfeet of astrocyte membrane, is considered a primary driver of the glymphatic clearance system, and defective AQP4-mediated glymphatic drainage has been linked to proteinopathies. The objective of the present review is to present the recent body of knowledge that links the glymphatic system to the pathogenesis of AD and PD disease and other lifestyle factors such as sleep deprivation and exercise that may influence glymphatic system function. We will also focus on the potential neuroimaging approaches that could identify a neuroimaging marker to detect glymphatic system changes.

Alzheimer’s disease (AD) is a neurodegenerative disorder accounting for over 50% of all dementia patients and representing a leading cause of death worldwide for the global ageing population. The lack of effective treatments for overt AD urges the discovery of biomarkers for early diagnosis, i.e., in subjects with mild cognitive impairment (MCI) or prodromal AD. The brain is exposed to oxidative stress as levels of reactive oxygen species (ROS) are increased, whereas cellular antioxidant defenses are decreased. Increased ROS levels can damage cellular structures or molecules, leading to protein, lipid, DNA, or RNA oxidation. Oxidative damage is involved in the molecular mechanisms which link the accumulation of amyloid-β and neurofibrillary tangles, containing hyperphosphorylated tau, to microglia response. In this scenario, microglia are thought to play a crucial role not only in the early events of AD pathogenesis but also in the progression of the disease. This review will focus on oxidative damage products as possible peripheral biomarkers in AD and in the preclinical phases of the disease. Particular attention will be paid to biological fluids such as blood, CSF, urine, and saliva, and potential future use of molecules contained in such body fluids for early differential diagnosis and monitoring the disease course. We will also review the role of oxidative damage and microglia in the pathogenesis of AD and, more broadly, in neurodegeneration.

In an ever-increasing aged world, Alzheimer’s disease (AD) represents the first cause of dementia and one of the first chronic diseases in elderly people. With 55 million people affected, the WHO considers AD to be a disease with public priority. Unfortunately, there are no final cures for this pathology. Treatment strategies are aimed to mitigate symptoms, i.e., acetylcholinesterase inhibitors (AChEI) and the N-Methyl-D-aspartate (NMDA) antagonist Memantine. At present, the best approaches for managing the disease seem to combine pharmacological and non-pharmacological therapies to stimulate cognitive reserve. Over the last twenty years, a number of drugs have been discovered acting on the well-established biological hallmarks of AD, deposition of β-amyloid aggregates and accumulation of hyperphosphorylated tau protein in cells. Although previous efforts disappointed expectations, a new era in treating AD has been working its way recently. The Food and Drug Administration (FDA) gave conditional approval of the first disease-modifying therapy (DMT) for the treatment of AD, aducanumab, a monoclonal antibody (mAb) designed against Aβ plaques and oligomers in 2021, and in January 2023, the FDA granted accelerated approval for a second monoclonal antibody, Lecanemab. This review describes ongoing clinical trials with DMTs and non-pharmacological therapies. We will also present a future scenario based on new biomarkers that can detect AD in preclinical or prodromal stages, identify people at risk of developing AD, and allow an early and curative treatment.

In the fascinating landscape of non-coding RNAs (ncRNAs), circular RNAs (circRNAs) are peeping out as a new promising and appreciated class of molecules with great potential as diagnostic and prognostic biomarkers. They come from circularization of single-stranded RNA molecules covalently closed and generated through alternative mRNA splicing. Dismissed for many years, similar to aberrant splicing by-products, nowadays, their role has been regained. They are able to regulate the expression of linear mRNA transcripts at different levels acting as miRNA sponges, interacting with ribonucleoproteins or exerting a control on gene expression. On the other hand, being extremely conserved across phyla and stable, cell and tissue specific, mostly abundant than the linear RNAs, it is not surprising that they should have critical biological functions. Curiously, circRNAs are particularly expressed in brain and they build up during aging and age-related diseases. These extraordinary peculiarities make circRNAs potentially suitable as promising molecular biomarkers, especially of aging and neurodegenerative diseases. This review aims to explore new evidence on circRNAs, emphasizing their role in aging and pathogenesis of major neurodegenerative disorders, Alzheimer’s disease, frontotemporal dementia, and Parkinson’s diseases with a look toward their potential usefulness in biomarker searching.

Although extracellular vesicles (EVs) were initially relegated to a waste disposal role, nowadays, they have gained multiple fundamental functions working as messengers in intercellular communication as well as exerting active roles in physiological and pathological processes. Accumulating evidence proves the involvement of EVs in many diseases, including those of the central nervous system (CNS), such as multiple sclerosis (MS). Indeed, these membrane-bound particles, produced in any type of cell, carry and release a vast range of bioactive molecules (nucleic acids, proteins, and lipids), conferring genotypic and phenotypic changes to the recipient cell. This means that not only EVs per se but their content, especially, could reveal new candidate disease biomarkers and/or therapeutic agents. This review is intended to provide an overview regarding current knowledge about EVs’ involvement in MS, analyzing the potential versatility of EVs as a new therapeutic tool and source of biomarkers.

Multiple sclerosis (MS) is the most prevalent demyelinating disease of the central nervous system (CNS) with an autoimmune component affecting young adults in their third decade of life. The etiology is still undefined, but myelin damage is mainly due to an aberrant immune response of lymphocyte cells against myelin components. Therefore, inflammation, demyelination, and axonal degeneration represent the major pathologic hallmarks of the disease. There are many risk factors associated with MS, and probably the most relevant is gender-related. Women are up to four times more affected than men are. Although the female prevalence in MS is epidemiologically evident, the identification of key factors involved in this difference is under investigation. On the other side, if women are more affected, men show late onset and worse prognosis. This sexual dimorphism derives from many sources, including sex hormones, different genes on female sex chromosomes, and differences in bacterial species. Indeed, accumulating evidence proves a link among MS and gut microbiota where its dysbiosis could help the immune system to trigger neuroinflammation. In this context, oral biology alteration should be considered, too. This work is intended to explore current knowledge inside MS gender differences with a look towards oral–gut–brain axis involvement.