Tracking and Predicting How Brain Damage Spreads in Neurodegenerative Diseases

April 30, 2026 updated by: Prof. Massimo Filippi, IRCCS San Raffaele

Tracking and Predicting Neurodegeneration Spreading Across the Brain Connectome

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.

Study Overview

Status

Enrolling by invitation

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

645

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
    • Lombardy
      • Milan, Lombardy, Italy, 20132
        • IRCCS San Raffaele

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

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:

  • Participants with a history of other neurological and/or psychiatric disorders, head trauma, alcohol or psychoactive substance use, or a family history of other neurodegenerative diseases.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Participants with the spectrum of FTLD, asymptomatic familiar, healthy elderly and young controls
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
3 Tesla MRI examination without contrast medium in which resting functional MRI sequences, diffusion-weighted sequence, structural MRI sequences will be obtained
Genetic: Blood sample for genetic analysis
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.
Diagnostic test: Cerebrospinal fluid sampling (CSF)
During the baseline visit, patients will undergo lumbar puncture for the collection of CSF for quantification of biological biomarkers
Diagnostic test: Neurological evaluation
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
Diagnostic test: Neuropsychological evaluation
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Longitudinal change in the structural connectome via Neurite Orientation Dispersion and Density Imaging (NODDI)
Time Frame: 6 months, 12 months, 18 months, 24 months
Evaluating structural white matter integrity over time through graph-theoretical analysis based on NODDI-derived metrics
6 months, 12 months, 18 months, 24 months
Longitudinal change in the structural connectome via Diffusion Tensor Imaging (DTI)
Time Frame: 6 months, 12 months, 18 months, 24 months
Evaluating structural white matter integrity over time through graph-theoretical analysis
6 months, 12 months, 18 months, 24 months
Longitudinal change in brain functional connectome via functional MRI
Time Frame: 6 months, 12 months, 18 months, 24 months
Evaluating functional brain changes in functional brain networks using graph-theoretical analysis of fMRI-derived connectivity
6 months, 12 months, 18 months, 24 months
Prediction of pathological spreading through the structural connectome
Time Frame: 6 months, 12 months, 18 months, 24 months
To predict spatial and temporal spreading of neurodegeneration through the structural connectome using network diffusion model
6 months, 12 months, 18 months, 24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

IRCCS San Raffaele

Collaborators

Istituto Auxologico Italiano
Azienda Ospedaliera San Gerardo di Monza
IRCCS Istituto delle Scienze Neurologiche di Bologna

Investigators

  • Study Director: Prof. Massimo Filippi, IRCCS San Raffaele

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 1, 2017

Primary Completion (Estimated)

February 15, 2027

Study Completion (Estimated)

March 1, 2027

Study Registration Dates

First Submitted

November 26, 2025

First Submitted That Met QC Criteria

April 30, 2026

First Posted (Actual)

May 5, 2026

Study Record Updates

Last Update Posted (Actual)

May 5, 2026

Last Update Submitted That Met QC Criteria

April 30, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • StG-2016_714388_NeuroTRACK_

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

Still undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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