An interventional study of 3 Tesla MRI without contrast medium and Blood sample for genetic analysis in Neurodegenerative Disease, Behavioral Variant Frontotemporal Dementia (bvFTD) and Primary Progressive Aphasia(PPA), sponsored by IRCCS San Raffaele. Enrolling by invitation at 1 site in Italy. Open to participants aged 20 Years to 85 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-05-05.
Sponsored by IRCCS San Raffaele · Not applicable, Interventional, and Diagnostic
Neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD) spectrum syndromes, are characterized by the accumulation of insoluble protein aggregates in the central nervous system. A common feature of these diseases is that pathological changes accumulate over time following a stereotyped spatial pattern, which contributes to the onset and progression of clinical symptoms. Until recently, the causes of such progression were still unknown. Recent pathological and neuroimaging studies have, however, suggested that insoluble and pathological protein aggregates are able to alter the conformation of neighboring proteins and spread through cell-to-cell transmission. According to this theory, called the 'brain connectome,' the brain network is established as a set of nodes, which correspond to different anatomical regions.
These brain networks are highly connected to each other and their internal organization is fundamental for an efficient integration of information coming from different regions and to guarantee adequate levels of motor/cognitive performance. Thanks to magnetic resonance studies and research in the field of brain networks, it is possible to understand the pathophysiology of neurodegenerative diseases and reveal the connectivity profiles associated with different clinical outcomes.
The main objective of this project is to explore the mechanisms of neurodegeneration associated with the different FTLD spectrum syndromes, and in particular the hypothesis that the neurodegenerative process is driven by the structural architecture of the brain 'connectome'. The ultimate goal is to apply mathematical models to structural and functional connectivity data to predict the evolution of the neurodegenerative process in sporadic and genetic forms of Frontotemporal Lobar Degeneration Disease.
This study aims to investigate the spatiotemporal progression of neurodegeneration in frontotemporal lobar degeneration (FTLD) using advanced neuroimaging and connectomics. 360 patients with sporadic FTLD (including bvFTD, semantic and nonfluent PPA, PSPs, CBS, and ALS) and 65 patients with genetic FTLD (MAPT, GRN, and C9orf72 mutati will be enrolled. The study also plans to enroll 120 subjects who are members of families carrying FLTD-associated mutations (including 60 mutation carriers). Finally, 100 healthy controls will also be enrolled, including 50 young healthy controls and 50 healthy controls comparable with patients by sex and age. Participants will undergo clinical, neuropsychological, and behavioral assessments, blood and Cerebrospinal fluid (CSF) collection, and multimodal 3Tesla Magnetic Resonance Imaging MRI at baseline and every 6 months for up to 2 years. Primary objectives include mapping longitudinal changes in structural and functional brain networks, developing predictive models of network degeneration and clinical decline, and characterizing protein-specific patterns of network degeneration. Secondary aims include identifying early network biomarkers in presymptomatic carriers and correlating network changes with biological markers.
370 studies on the registry are indexed under Neurodegenerative Diseases; 145 are open to participants now.
This study's planned enrollment of 645 is above the median of 53 across 204 interventional studies indexed under Neurodegenerative Diseases.
Browse Neurodegenerative Diseases studies →IRCCS San Raffaele is the lead sponsor of 443 studies on the registry; 234 are open to participants now.
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Adult participants, under 85 years of age, diagnosed with bvFTD, semantic variant PPA, non-fluent variant PPA, PSP, CBS, and early-stage ALS, according to the criteria of Rascovsky (2011), Gorno-Tempini (2011), Litvan (1996), Armstrong (2013), and Brooks (2000), respectively;
Participants with genetic forms of FTLD associated with mutations in the c9orf72, GRN, MAPT genes, and asymptomatic family members related to FTLD patients carrying such mutations
Healthy participants (age between 20 and 30 years old); Healthy participants matched to patients for age and sex
Exclusion Criteria:
Partecipants affected by behavioral variant of FTLD (bvFTD), primary progressive aphasia (PPA), semantic variant of PPA (svPPA), non-fluent variant of PPA (nfvPPA), progressive supranuclear paralysis (PSP), corticobasal syndrome (CBS), amyotrophic lateral sclerosis (ALS), genetic and sporadic FTLD. Asymptomatic familiar. Healthy elderly and young controls.
Diagnostic Test: 3 Tesla MRI without contrast medium · Genetic: Blood sample for genetic analysis · Diagnostic Test: Cerebrospinal fluid sampling (CSF) · Diagnostic Test: Neurological evaluation · Diagnostic Test: Neuropsychological evaluation
3 Tesla MRI examination without contrast medium in which resting functional MRI sequences, diffusion-weighted sequence, structural MRI sequences will be obtained
During the screening/basal visit, a blood sample will be taken to assess the genetic profile of patients, consanguineous family members, and healthy elderly controls. Objective is to evaluate the major genes that have been shown to play a role in the pathogenesis of FTLD The genes GRN, MAPT, C9orf72, TARDBP, SOD1, FUS, OPTN, VCP will be analyzed.
During the baseline visit, patients will undergo lumbar puncture for the collection of CSF for quantification of biological biomarkers
A neurological evaluation will be conducted in order to be able to exclude from the study all participants with a history of psychiatric illness, head injury, alcohol or psychotropic substance use
A neuropsychological assessment will be conducted in order to be able to exclude from the study all participants with a history of psychiatric illness, alcohol or psychotropic substance use
Longitudinal change in the structural connectome via Neurite Orientation Dispersion and Density Imaging (NODDI)
Evaluating structural white matter integrity over time through graph-theoretical analysis based on NODDI-derived metrics
Time frame: 6 months, 12 months, 18 months, 24 months
Longitudinal change in the structural connectome via Diffusion Tensor Imaging (DTI)
Evaluating structural white matter integrity over time through graph-theoretical analysis
Time frame: 6 months, 12 months, 18 months, 24 months
Longitudinal change in brain functional connectome via functional MRI
Evaluating functional brain changes in functional brain networks using graph-theoretical analysis of fMRI-derived connectivity
Time frame: 6 months, 12 months, 18 months, 24 months
Prediction of pathological spreading through the structural connectome
To predict spatial and temporal spreading of neurodegeneration through the structural connectome using network diffusion model
Time frame: 6 months, 12 months, 18 months, 24 months
Plan to share: Undecided — Still undecided
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