Frontotemporal dementia (FTD) is a neurodegenerative disease of growing interest, since it accounts for up to 10% of middle-age-onset dementias and entails a social, economic, and emotional burden for the patients and caregivers. It is characterised by a (at least initially) selective degeneration of the frontal and/or temporal lobe, generally leading to behavioural alterations, speech disorders, and psychiatric symptoms. Despite the recent advances, given its extreme heterogeneity, an overview that can bring together all the data currently available is still lacking. Here, we aim to provide a state of the art on the pathogenesis of this disease, starting with established findings and integrating them with more recent ones. In particular, advances in the genetics field will be examined, assessing them in relation to both the clinical manifestations and histopathological findings, as well as considering the link with other diseases, such as amyotrophic lateral sclerosis (ALS). Furthermore, the current diagnostic criteria will be explored, including neuroimaging methods, nuclear medicine investigations, and biomarkers on biological fluids. Of note, the promising information provided by neurophysiological investigations, i.e., electroencephalography and non-invasive brain stimulation techniques, concerning the alterations in brain networks and neurotransmitter systems will be reviewed. Finally, current and experimental therapies will be considered.

The dysfunction of cholinergic neurons is a typical hallmark in Alzheimer's disease (AD). Previous findings demonstrated that high density of cholinergic receptors is found in the thalamus and the cerebellum compared with the cerebral cortex and the hippocampus. We aimed at investigating whether activation of the cerebello-thalamo-cortical pathway by means of cerebellar theta burst stimulation (TBS) could modulate central cholinergic functions evaluated in vivo by using the neurophysiological determination of Short-Latency Afferent Inhibition (SLAI). We tested the SLAI circuit before and after administration of cerebellar continuous TBS (cTBS) in 12 AD patients and in 12 healthy age-matched control subjects (HS). We also investigated potential changes of intracortical circuits of the contralateral primary motor cortex (M1) by assessing short intracortical inhibition (SICI) and intracortical facilitation (ICF). SLAI was decreased in AD patients compared to HS. Cerebellar cTBS partially restored SLAI in AD patients at later inter-stimulus intervals (ISIs), but did not modify SLAI in HS. SICI and ICF did not differ in the two groups and were not modulated by cerebellar cTBS. These results demonstrate that cerebellar magnetic stimulation is likely to affect mechanisms of cortical cholinergic activity, suggesting that the cerebellum may have a direct influence on the cholinergic dysfunction in AD.

Background: Alzheimer’s disease (AD) is the leading cause of dementia worldwide, and cost-effective tools to detect amyloid pathology are urgently needed. Blood-based Tau phosphorylated at threonine 217 (pTau217) seems promising, but its reliability as a proxy for cerebrospinal fluid (CSF) status and ability to identify patients within the AD spectrum remain unclear. Methods: We performed a systematic review and meta-analysis on the potential of blood pTau217 to differentiate amyloid-positive (A+) and amyloid-negative (A−) subjects. We included original studies reporting quantitative data on pTau217 concentrations in both blood and CSF in the AD continuum. The single-group meta-analysis computed the pooled pTau217 levels in blood and in CSF, separately in the A+ and A− groups, while the head-to-head meta-analysis compared the mean pTau217 concentrations in the A+ versus A− subjects, both in blood and CSF, stratifying by assessment method in both cases. Results: Ten studies (819 A+; 1055 A−) were included. The mean pTau217 levels resulted higher in CSF than in blood and, crucially, in A+ individuals than in A– ones, regardless of the laboratory method employed. Most importantly, all laboratory techniques reliably distinguished A+ from A– subjects, whether applied to CSF or blood samples. Conclusions: These results confirm that blood-based pTau217 is a reliable marker of amyloid pathology with significant implications for clinical practice in the AD continuum. Indeed, pTau217 might be a non-invasive, scalable biomarker for early AD detection, reducing the reliance on more invasive, expansive, and less accessible methods. Clinical trial registration: Prospero CRD42024565187

Increasing evidence strongly supports the key role of neuroinflammation in the pathophysiology of neurodegenerative diseases, such as Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Neuroinflammation may alter synaptic transmission contributing to the progression of neurodegeneration, as largely documented in animal models and in patients’ studies. In the last few years, palmitoylethanolamide (PEA), an endogenous lipid mediator, and its new composite, which is a formulation constituted of PEA and the well-recognized antioxidant flavonoid luteolin (Lut) subjected to an ultra-micronization process (co-ultraPEALut), has been identified as a potential therapeutic agent in different disorders by exerting potential beneficial effects on neurodegeneration and neuroinflammation by modulating synaptic transmission. In this review, we will show the potential therapeutic effects of PEA in animal models and in patients affected by neurodegenerative disorders.

INTRODUCTION: Blood‐based biomarkers seem promising for the diagnosis of Alzheimer's disease (AD).METHODS: We performed a systematic review and meta‐analysis on the potential of blood phosphorylated Tau181 (p‐tau181) to differentiate amyloid‐positive (A+) and amyloid‐negative (A−) subjects. Two meta‐analyses were conducted, showing the mean p‐tau values in blood and cerebrospinal fluid (CSF) in the A+ and A− group, and the second comparing the mean p‐tau concentrations in blood and CSF among A+ versus A‐ participants, by laboratory assessment method.RESULTS: Eighteen studies (2764 A+ and 5646 A− subjects) were included. The single‐group meta‐analysis showed mean higher blood p‐tau181 values in the A+ than in the A− group. In the head‐to‐head meta‐analysis, blood p‐tau reliably differentiated A+ patients from A− participants.DISCUSSION: Regardless of the laboratory technique, blood p‐tau181 reliably differentiates A+ and A− subjects. Therefore, it might have important applications for early diagnosis and inclusion in clinical trials for AD patients.Highlights: The role of blood‐based biomarkers in discriminating AD patients is still uncertain. Blood p‐tau181 distinguishes among amyloid‐positive and amyloid‐negative subjects. Blood p‐tau181 might allow early diagnosis and inclusion in clinical trials.