Optical Imaging in X-linked Disorders.

Official title

Optical Imaging as a Diagnostic Tool for Monitoring Brain Function in X-linked Rare Disorders

Overview

Fragile X syndrome (FXS, OMIM #300624) and Creatine Transporter Deficiency (CTD, #300352) are the two most common causes of X-linked intellectual disability. FXS and CTD affect hemizygous males and with highly variable severity heterozygous females. Both these neurodevelopmental disorders (NDDs) have a dramatic impact on the family quality of life and the health-care system. These disorders share common clinical traits, including intellectual disability, autistic-like features, behavioural and mood alterations and seizures. Brain anatomy appears largely normal, suggesting that functional deficits result from subtle changes in synaptic connectivity. Moreover, common physiological mechanisms related to brain energetics might concur to the pathophysiology of FXS and CTD. Indeed, FMR1 and SLC6A8 are directly involved in the regulation of metabolism and the loss-of-function of both genes leads to a disruption of the mitochondrial network. There is no cure for these disorders and the efficacy study of potential treatments is hindered by the scarcity of unbiased, quantitative, non-invasive biomarkers for monitoring brain function. This is a critical problem, since the often-used phenotypic observation of behavioural endpoints to score NDDs such as FXS and CTD is highly prone to subjective bias. For successful clinical trials, the availability of objective readouts is crucial to evaluate the therapeutic response to new drugs. There are multiple techniques to visualize neural circuit activity in the living brain. Interestingly, FXS and CTD are the only two NDDs that at preclinical level show an abnormally large hemodynamic response to sensory stimulation in functional imaging studies of intrinsic optical signals. The objective of this project is to exploit optical imaging techniques to devise a measurable and non-invasive biomarker of brain function in FXS and CTD. Since a disruption of brain energy metabolism is a major disease mechanism linking these disorders, we hypothesized that the assessment of the cerebral blood flow and oxygen consumption represents a sensitive readout for quantifying functional alterations of neural circuits. Functional near-infrared spectroscopy (fNIRS), allows quantifying changes of hemoglobin species and local blood flow in the cerebral cortex of humans, providing an indirect measure of neuronal activity. In the clinical framework, this blood-oxygen-level-dependent signal is similar to that detected with functional MRI (fMRI). However, fNIRS has the advantage of being completely non-invasive, low-cost, portable, noiseless, endowed with high experimental flexibility and easy to implement in both laboratory and clinical settings. Moreover, fNIRS is more tolerant to motion artifacts than fMRI, and robust methods for motion detection/correction allow to image very young children without sedation. These methodological strengths make fNIRS as an outstanding choice for investigating neural circuits in clinically relevant populations at the very-low cost. Although introduced into the clinical care almost 40 years ago, fNIRS gained much popularity in the study of brain development and NDDs only recently. To date, however, fNIRS has been used primarily to investigate the typical maturation of speech perception and language, sensory and motor functions, social communication and interaction, object and action processing in toddlers and children. In this proposal, the investigators hypothesize that by combining the above-mentioned strengths of fNIRS to the clinical study of several cognitive and motor parameters, the investigators can define unique "fNIRS signatures" for FXS and CTD as brain biomarkers for the diagnosis and the assessment of treatment outcomes. Since the measurement of visual responses has been introduced as a quantitative method to assess brain function in NDDs, the investigators will test the value of visually-evoked fNIRS signals in classifying patients and predicting symptom severity in the FXS and CTD clinical population. Preliminary data in the mouse models of CTD and FXS strongly suggest that visual hemodynamic responses (vHDR) are markedly altered in the occipital cortex of mutant animals. Morever, the investigators will use a standardized procedure with high entertaining value to measure vHDR in the occipital cortex of children.

Interventions

• Other Clinical assessment
  Clinical examination including Medical history, developmental trajectory, epilepsy history, ASD symptoms, clinical examination at the inclusion visit by a neuropediatrist
• Other Parental questionnaires
  Parental questionnaires including Vineland-2, ABC, CBCL, PPD-MRS, SRS-2 and BRIEF completed at the inclusion visit
• Other Cognitive assessment
  Cognitive assessment including Leiter-3, PPVT 5, EVT 3 completed at the inclusion visit
• Other Reasoning assessment
  Simple reasoning tasks on tablets performed at the inclusion visit.
• Device fNIRS assessement
  Imaging session using fNIRS (NIRSport 8x8, NIRx Medical Technologies LLC, Berlin, Germany) performed at the inclusion visit.

Primary outcome measures

• Amplitude of the visual hemodynamic response [Time frame: Inclusion visit]
• Latency of the visual hemodynamic response [Time frame: Inclusion visit]

Secondary outcome measures (12)

• Clinical Endpoints_Presence of epilepsy [Time frame: Inclusion visit]
• Clinical Endpoints_Type of epilepsy [Time frame: Inclusion visit]
• Clinical Endpoints_Treatment of epilepsy [Time frame: Inclusion visit]
• Clinical endpoints_Developmental trajectory [Time frame: Inclusion visit]
• Clinical endpoints_Autism spectrum disorder (ASD) [Time frame: Inclusion visit]
• Cognitive assessment with Leiter 3 scale [Time frame: Inclusion visit]
• Cognitive assessment with Bayley 4 scale [Time frame: Inclusion visit]
• Language assessment with the PPVT-5 test [Time frame: Inclusion visit]
• Language assessment with the EVT-3 test [Time frame: Inclusion visit]
• Reasoning tasks [Time frame: Inclusion visit]
• Parental questionnaires to assess adaptive abilities (Vineland 2) [Time frame: Inclusion visit]
• Parental questionnaires to assess behavioral disorder (ABC 2) [Time frame: Inclusion visit]

Eligibility criteria

Inclusion criteria

CTD male patients :

• male
• having a confirmed mutation in the SLC6A8 gene
• ≥ 5 to ≤ 35 years old
• whose maternal language is French,
• having signed the informed consent and/or for whom parents (for children)/legal guardian (for protected adults) have signed the informed consent.
• affiliated to national Health Insurance system (sécurité sociale) or parents/legal guardian affiliated to national health insurance system

CTD female patients :

• female CTD patients having a confirmed mutation in the SLC6A8 gene,
• aged > 5 to < 60 years,
• whose maternal language is French (for the patients included in France),
• having signed the informed consent and/or for whom parents (for children)/legal guardian (for protected adults) have signed the informed consent.
• affiliated to national Health Insurance system (sécurité sociale) or parents/legal guardian affiliated to national health insurance system

FXS patients :

• male
• having a confirmed full mutation in the FMR1 gene (>200 GCC repeats)
• ≥ 5 to ≤ 35 years old
• whose maternal language is French,
• having signed the informed consent and/or for whom parents (for children)/legal guardian (for protected adults) have signed the informed consent.
• affiliated to national Health Insurance system (sécurité sociale) or parents/legal guardian affiliated to national health insurance system

Sex- and chronological age-matched male controls :

• male
• ≥ 5 to ≤ 35 years old
• whose maternal language is French,
• having signed the informed consent and/or for whom parents have signed the informed consent.
• affiliated to national Health Insurance system (sécurité sociale) or parents/legal guardian affiliated to national health insurance system

Sex- and chronological age-matched female controls :

• female,
• aged > 5 to < 60 years
• whose maternal language is French (for the patients included in France),
• having signed the informed consent and/or for whom parents/legal guardian have signed the informed consent.
• affiliated to national Health Insurance system (sécurité sociale) or parents/legal guardian affiliated to national health insurance system.

Each CTD patient will be matched to a sex- and chronological age-matched control.

Exclusion criteria

CTD male and female patients :

• Refusal of the subject and/or the subject's parents/legal guardian to sign the informed consent
• Refusal of the subject and/or the subject's parents/legal guardian to be informed of possible abnormalities detected during the neuropsychological assessment.

FXS patients :

• Refusal of the subject and/or the subject's parents/legal guardian to sign the informed consent
• Refusal of the subject and/or the subject's parents/legal guardian to be informed of possible abnormalities detected during the neuropsychological assessment.

Sex- and chronological age-matched male and female controls :

• Refusal of the subject and/or the subject's parents/legal guardian to sign the informed consent
• Refusal of the subject and/or the subject's parents/legal guardian to be informed of possible abnormalities detected during the neuropsychological assessment.
• History of neurological or psychiatric disorder,
• Repetition of a grade,
• Learning disability requiring rehabilitation (speech therapy, psychomotor or oculomotor therapy).

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

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Other

Study locations

France · 1 center

• Woman, mother and child hospital, Hospices Civils de Lyon — Bron

Identifiers

NCT: NCT06868979 · 69HCL23_0409 · 2024-A01730-47

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗