Clinical Research Directory

Disease Biosignatures in ALS/FTD Spectrum: New Impactful Biological Perspectives Beyond Clinical Approaches

Diagnosis of ALS/FTD disease spectrum is challenging because it largely relies on clinical symptoms. Identifying novel biomarkers is essential for a paradigm shift towards a more precise biological-based diagnosis. To achieve this aim, having access to proper specimens and analytical methods is crucial. Our team of experts in neurology, biology, chemistry, physics, and AI will explore ALS/FTD from novel perspectives using transcriptomics, proteomics, genomics and other innovative approaches to analyzing easily accessible tissues. The seed amplification assay (SAA) will be also exploited to detect pathological TDP-43. This project aims to create disease fingerprints useful for patient stratification and monitoring of disease progression, and to evaluate the therapeutic efficacy in clinical trials, thus overcoming the limits of clinical interpretation. Discovering new biomarkers and cellular pathways will improve the diagnosis and treatment of these devastating diseases.

A Study to Evaluate the Safety and Effect of AVB-101, a Gene Therapy Product, in Subjects With a Genetic Sub-type of Frontotemporal Dementia (FTD-GRN)

The goal of this clinical study is to learn about an investigational gene therapy product called AVB-101, which is designed to treat a disease called Frontotemporal Dementia with Progranulin Mutations (FTD-GRN). FTD-GRN is an early-onset form of dementia, a progressive brain disorder that affects behavior, language and movement. These symptoms result from below normal levels of a protein called progranulin (PGRN) in the brain, which leads to the death of nerve cells (neurons), affecting the brain's ability to function. The main questions that the study aims to answer are: 1. Is a one-time treatment with AVB-101 safe for patients with FTD-GRN? 2. Does a one-time treatment with AVB-101 restore PGRN levels to at least normal levels? 3. Could AVB-101 work as a treatment to slow down or stop progression of FTD-GRN? In this study there is no placebo (a dummy pill or treatment used for comparison purposes), so all participants will receive a one-time treatment of AVB-101 delivered directly to the brain, with follow-up assessments for 5 years.

A Multi-Modal Remote Monitoring Platform for Frontotemporal Lobar Degeneration (FTLD) Syndromes

The primary objective of this study is to enroll an observational cohort of approximately 60 patients with PSP over the course of 24 months using a multicenter study design and to follow each of them for 12 months. The secondary objective of this study is to develop a robust solution for multi-modal remote monitoring of motor symptoms and function in PSP that can be applied to other Frontotemporal lobar degeneration (FTLD) syndromes.

Repetitive Transcranial Magnetic Stimulation in Frontotemporal Lobar Degeneration

The aim of the study is to evaluate the safety, feasibility, clinical and biological efficacy, and predictors of efficacy of an intervention consisting of repetitive transcranial magnetic stimulation (rTMS) in patients with frontotemporal dementia (FTLD) or in asymptomatic persons at risk of FTLD (i.e., persons familiar with FTLD patients). rTMS is a non-invasive brain stimulation technique, and has demonstrated the ability to modulate neuronal activity by applying high-frequency magnetic fields to the surface of the skull. rTMS offers a potentially effective means to influence neural networks involved in the pathogenesis of neurodegenerative diseases, with benefits that could extend beyond symptomatic relief. Its safety has been widely documented in a variety of clinical conditions, making it an ideal candidate for application in neurodegenerative diseases. In the present study, participants will undergo the following procedures: (i) clinical and neuropsychological assessment, (ii) TMS, and (iii) blood sampling. The occurrence of adverse events will be monitored throughout the duration of the study. The study is structured in two phases. In the first phase, double-blind, randomised and placebo-controlled, participants will be randomised into two groups: group 1, participants will receive real rTMS for 2 weeks; and group 2, placebo rTMS for 2 weeks. In the second, open-label phase, after 10 weeks, both group 1 and group 2 participants will receive real rTMS for 2 weeks. Each participant will receive a total of 4 weeks of intervention (4 weeks of real stimulation in group 1, or 2 weeks of real stimulation and 2 weeks of placebo stimulation in group 2), with 5 sessions per week (Monday to Friday) lasting approximately 30 minutes each. Visits will take place at the beginning of the study (T00) and after 2 weeks (T02, end of the first phase), 12 weeks (T12, beginning of the second phase), 14 weeks (T14, end of the second phase), 24 weeks (T24, follow-up). During each visit, participants underwent the following procedures: (i) clinical and neuropsychological assessment, (ii) blood sampling, and (iii) TMS. Specific biomarker analyses will be performed on the blood samples to study the pathophysiological mechanisms of the disease and the effect of the experimental intervention.

A Study of PBFT02 in Participants With FTD and Mutations in the Granulin Precursor (GRN) or C9ORF72 Genes

PBFT02 is a gene therapy for frontotemporal dementia intended to deliver a functional copy of the GRN gene to the brain. This study will assess the safety, tolerability and efficacy of this treatment in patients with frontotemporal dementia and mutations in the granulin precursor (GRN) or chromosome 9 open reading frame 72 (C9ORF72) genes

Omics Sciences for the Identification of Pathogenetic Mechanisms and Biomarkers in Neurodegenerative Diseases

The study aims to use 'omics' sciences, employing the most advanced technologies currently available, in order to identify pathogenic genomic variants, proteins and/or altered molecular pathways in neurodegenerative diseases and to obtain a new and more complete characterisation of subjects affected by the neurodegenerative diseases under study. Thanks to the integration of genomic, gene expression (transcriptomic and epigenomic), protein and metabolic data and clinical data, the study also aims to identify new markers for the diagnosis, prognosis, also in terms of response to therapy, and monitoring of neurodegenerative diseases. The study involves the enrolment of at least 1.200 individuals with neurodegenerative disease.

Clinico-Pathologic-Genetic-Imaging Study of Neurodegenerative and Related Disorders

The investigators aim to learn more about symptoms suggestive of a neurodegenerative process.

Neurofilament Surveillance Project (NSP)

This is a biomarker study designed to collect and analyze blood specimens from individuals carrying known familial frontotemporal lobar degeneration (f-FTLD) mutations compared to a control group of individuals without known f-FTLD mutations. The NSP is an ancillary study to the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration" (ALLFTD) study, NCT04363684. More information can be found at https://www.allftd.org/.

Metabolic Characterization of Alzheimer's Disease and Frontotemporal Dementia by 23Na-MRI and FDG-PET

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the most common forms of neurodegenerative dementia. However, their differential and timely diagnosis can be challenging for clinicians, therefore often closing the door for an early and possibly successful treatment before irreversible cerebral damage occurs. Hence, treatment options often become available only at a late point in time. In Alzheimer's disease, early neuroimaging markers are glucose hypometabolism and Amyloid-/Tau-depositions (PET). Recent findings from sodium magnetic resonance imaging (23Na-MRI) point to brain tissue sodium concentration as a metabolic marker of AD progression. Sodium is crucial for neurotransmission and cellular homeostasis maintained by the cellular Na+/K+-ATPase, depending on Adenosine-Triphosphate as energy source from the mitochondrial respiratory chain, also interacting with tau and amyloid. In this project, we aim to characterize disease-specific metabolic patterns in AD vs. FTD by performing 23Na-MRI in association to FDG-PET to support early positive and differential diagnosis and therapeutic follow-up in both diseases in association to clinical parameters such as CSF/blood markers and neuropsychological assessment. Assessment of 7T MRI including 23Na-MRI, 31P-MRS and 1H-MRI is planned with analysis of results in association with FDG-PET, Amyloid- and Tau-PET, blood and CSF biomarkers as well as neuropsychological and clinical assessment.

Neurofilament Light Chains and Cognitive Impairment in Chronic Psychiatric Disease

The validation of biomarkers allowing the discrimination of cognitive and behavioral disorders of psychiatric origin from those of neurodegenerative origin would facilitate diagnosis and improve patient management. Neurofilaments, which are markers of neuronal lysis, appear to be a promising biomarker. In a previous preliminary study, the investigators demonstrated significantly lower concentrations of neurofilaments in CSF of psychiatric patients compared to neurodegenerative diseases. The main objective of this study is to validate the plasma assay of neurofilament light chain as a biomarker for the differential diagnosis of psychiatric or neurodegenerative cognitive impairment. Other biomarkers of interest (Tau, TDP-43, GFAP and UCH-L1) will also be analyzed. A sub-part of this study will also focus on the retrospective analysis of the CSF/Plasma correlations of the different biomarkers mentioned above from tube bottom samples taken in routine care.

Nabilone for Agitation in Frontotemporal Dementia

The primary goal of this study is to test the hypothesis that oral nabilone treatment will reduce agitation compared with placebo in patients with Frontotemporal Dementia (both behavioural variant frontotemporal dementia and primary progressive aphasia). The study population is defined as patients with probable Frontotemporal Dementia that meet the International Psychogeriatric Association criteria for agitation in cognitive disorders.

Genetics and Environment iNtersection In the ALS-FTD Spectrum: an Italian Twins Cohort studY With a Multi-Omics Approach

The goal of this study is to learn from discordant twins affected by Amyotrophic Lateral Sclerosis and/or Frontotemporal Dementia the contribution of genetic background versus environmental exposure. The main questions it aims to answer is: * How far does the genetic background explain the onset of ALS/FTD in discordant twins? * Which environmental factors and events occurring in post-fetal life influence the onset or progression of this neurodegenerative condition? Participants with ALS and/or FTD with a monozygotic or dizygotic twin willing to contribute to this research will be followed up for two years by specialized Motor Neuron Disorders centers in Italy, donating biological specimen for -omic sciences analysis, and checking out if prodromal signs/symptoms of these two conditions will develop during time.