Federica Perrone

Frontotemporal dementia (FTD) is the second most common cause of early‐onset dementia after Alzheimer's disease, characterized by substantial genetic, clinical, and pathological heterogeneity. Despite progress in understanding its pathophysiology, no disease‐targeted therapies (DTTs) have been approved to date. This study provides an updated overview of ongoing and completed clinical trials in FTD, analyzing therapeutic strategies, trial phases, and molecular targets. All registered trials were systematically searched on the online registers ClinicalTrials.gov, the EU Clinical Trials Register, and the International Clinical Trials Registry Platform, using the search terms “Frontotemporal Dementia,” “FTD,” and “svPPA” (semantic variant primary progressive aphasia). Included studies investigated pharmacological or cell‐based interventions in Phases 1 through 4 or in trials with no reported phase. Non‐pharmacological and biomarker‐only trials were excluded. The Common Alzheimer's Disease Research Ontology (CADRO) was used to classify mechanisms of action. Data were collected as of February 3, 2026. A total of 49 trials were identified, investigating 35 pharmacological and three cell interventions. Among them, 16 trials (32.7%) were still active and had an expected sample size of 1036 participants. More than half of the pharmacological interventions investigated were classified as DTTs (67.3%), targeting specifically GRN ‐ and C9orf72 ‐associated genetic forms of FTD, while 26.5% targeted symptomatic treatments, addressing behavioral and neuropsychiatric symptoms. Seventeen molecules (32.7%) were repurposed drugs. The pipeline for the development of new potential treatments for FTD is still limited, with a predominant focus on rare genetic forms and a limited number of trials addressing sporadic FTD. Many trials remain inactive or unpublished, hindering translational progress. The scarcity of reliable biomarkers and the exclusion of patients without access to genetic testing further limits trial inclusivity. Improving biomarker research, trial transparency, and global accessibility are critical steps toward developing effective, scalable therapies for FTD.

Tau-associated microRNAs have been implicated in neurodegenerative disorders, yet their behavior during SARS-CoV-2 infection remains insufficiently understood. The aim of this study was to quantify circulating levels of miR-92a-3p, miR-320a, and miR-320b in hospitalized COVID-19 patients and evaluate their relationship with disease severity and established biomarkers of neuroinflammation and neurodegeneration. We conducted a retrospective single-center study including 38 hospitalized COVID-19 patients and 12 healthy controls. MicroRNA plasma levels were quantified by RT-qPCR. Patients were stratified by ARDS severity and ventilation requirements. Correlations between miRNAs and previously published biomarkers were examined. All three miRNAs were elevated in COVID-19 patients compared to healthy controls. miR-92a-3p and miR-320a were increased in both severe and non-severe cases, while miR-320b was significantly elevated only in severe disease. No statistically significant correlations were observed between miRNA levels and NfL, GFAP, MMP-9, or other biomarkers in COVID-19 patients. Tau-associated circulating microRNAs appear dysregulated in acute SARS-CoV-2 infection, but their relationship to neurological injury remains unclear. These findings are preliminary and require validation in larger, longitudinal cohorts with standardized neurological outcomes.

Whether as a cause or a symptom, RNA transcription is recurrently altered in pathologic conditions. This is also true for non-coding RNAs, with regulatory functions in a variety of processes such as differentiation, cell identity and metabolism. In line with their increasingly recognized roles in cellular pathways, RNAs are also currently evaluated as possible disease biomarkers. They could be informative not only to follow disease progression and assess treatment efficacy in clinics, but also to aid in the development of new therapeutic approaches. This is especially important for neurological and genetic disorders, where the administration of appropriate treatment during the disease prodromal stage could significantly delay, if not halt, disease progression. In this review we focus on the current status of biomarkers in Huntington’s Disease (HD), a fatal hereditary and degenerative disease condition. First, we revise the sources and type of wet biomarkers currently in use. Then, we explore the feasibility of different RNA types (miRNA, ncRNA, circRNA) as possible biomarker candidates, discussing potential advantages, disadvantages, sources of origin and the ongoing investigations on this topic.

Knowledge of the molecular etiology of neurodegenerative brain diseases (NBD) has substantially increased over the past three decades. Early genetic studies of NBD families identified rare and highly penetrant deleterious mutations in causal genes that segregate with disease. Large genome-wide association studies uncovered common genetic variants that influenced disease risk. Major developments in next-generation sequencing (NGS) technologies accelerated gene discoveries at an unprecedented rate and revealed novel pathways underlying NBD pathogenesis. NGS technology exposed large numbers of rare genetic variants of uncertain significance (VUS) in coding regions, highlighting the genetic complexity of NBD. Since experimental studies of these coding rare VUS are largely lacking, the potential contributions of VUS to NBD etiology remain unknown. In this review, we summarize novel findings in NBD genetic etiology driven by NGS and the impact of rare VUS on NBD etiology. We consider different mechanisms by which rare VUS can act and influence NBD pathophysiology and discuss why a better understanding of rare VUS is instrumental for deriving novel insights into the molecular complexity and heterogeneity of NBD. New knowledge might open avenues for effective personalized therapies.

Background: Alzheimer’s disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic Aβ peptides. Amongst these, Aβ_1–43 is more prone to aggregation and has higher toxic properties than the long-known Aβ_1–42. However, a direct effect on Aβ_1–43 in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined. Methods: N = 1431 AD patients (n = 280 early-onset (EO) and n = 1151 late-onset (LO) AD) and 809 control individuals were genetically screened for APP and PSENs. For the first time, Aβ_1–43 levels were analysed in cerebrospinal fluid (CSF) of 38 individuals carrying pathogenic or unclear rare mutations or the common PSEN1 p.E318G variant and compared with Aβ_1–42 and Aβ_1–40 CSF levels. The soluble sAPPα and sAPPβ species were also measured for the first time in mutation carriers. Results: A known pathogenic mutation was identified in 5.7% of EOAD patients (4.6% PSEN1, 1.07% APP) and in 0.3% of LOAD patients. Furthermore, 12 known variants with unclear pathogenicity and 11 novel were identified. Pathogenic and unclear mutation carriers showed a significant reduction in CSF Aβ_1–43 levels compared to controls (p = 0.037; < 0.001). CSF Aβ_1–43 levels positively correlated with CSF Aβ_1–42 in both pathogenic and unclear carriers and controls (all p < 0.001). The p.E318G carriers showed reduced Aβ_1–43 levels (p < 0.001), though genetic association with AD was not detected. sAPPα and sAPPβ CSF levels were significantly reduced in the group of unclear (p = 0.006; 0.005) and p.E318G carriers (p = 0.004; 0.039), suggesting their possible involvement in AD. Finally, using Aβ_1–43 and Aβ_1–42 levels, we could re-classify as “likely pathogenic” 3 of the unclear mutations. Conclusion: This is the first time that Aβ_1–43 levels were analysed in CSF of AD patients with genetic mutations in the AD causal genes. The observed reduction of Aβ_1–43 in APP and PSENs carriers highlights the pathogenic role of longer Aβ peptides in AD pathogenesis. Alterations in Aβ_1–43 could prove useful in understanding the pathogenicity of unclear APP and PSENs variants, a critical step towards a more efficient genetic counselling.