Tracking and Predicting How Brain Damage Spreads in Neurodegenerative Diseases

Official title

Tracking and Predicting Neurodegeneration Spreading Across the Brain Connectome

Overview

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.

Interventions

• 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

Primary outcome measures

• Longitudinal change in the structural connectome via Neurite Orientation Dispersion and Density Imaging (NODDI) [Time frame: 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]
• Longitudinal change in brain functional connectome via functional MRI [Time frame: 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]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Diagnostic

Study locations

Italy · 1 center

• IRCCS San Raffaele — Milan

Identifiers

NCT: NCT07567664 · StG-2016_714388_NeuroTRACK_

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗