Choroid Plexus Dysfunction in Neurological Diseases
Profound Cerebral Folate Deficiency as a Clinical Model for Identification of MRI and Biochemical Signatures of Choroid Plexus Dysfunction
Assistance Publique - Hôpitaux de Paris
65 participants
Jan 20, 2025
INTERVENTIONAL
Conditions
Summary
Cerebral folate deficiency (CFD), a partially treatable condition defined by a low folate cerebrospinal fluid (CSF) concentration, can be linked to genetic defects of folate metabolism or be secondary to various diseases without clear causal link. The team identified a neurological syndrome (named LHIPFOLFD) characterized by deep CFD and a specific leukoencephalopathy, related to several possible gene defects never involving folate metabolism. The team hypothesize that CFD in LHIPFOLD is due to a Choroid Plexus (CP) dysfunction, a brain organ that expresses transporters regulating flux between blood and CSF of numerous metabolites (including folate), and secretes CSF and specific proteins. Consequently, other potentially treatable biochemical abnormalities due to PC dysfunction may exist in LHIPFOLD, beyond CFD. Currently, there is no available clinical explorations to evaluate CP functions, whereas the team consider LHIPFOLD a very useful model to validate the capacity of some relevant diagnostic tools to do so. The objectives are to identify a CP-related MRI and biochemical signature in LHIPFOLD patients, using morphological and functional imaging (CP capillary permeability and CP macrovascular perfusion), and metabolomics/proteomics approaches (untargeted then targeted validation of candidate biomarkers related to CP physiology); and to set-up imaging and biochemical diagnostic tests for clinical practice. For this, brain MRI data and blood/CSF samples will be collected during 2 years from LHIPFOLD patients and controls. Some experimental data indicate that the innovative concept of generalized PC dysfunction as part of a more global pathophysiology has the potential to be applied to other neurological diseases like Alzheimer's disease. Therefore, efficient diagnostic tools exploring CP function will be of great utility not only in LHIPFOLD but also in more common neurological diseases, potentially leading to original therapeutic approaches.
Eligibility
Inclusion Criteria12
- For LHIPFOLD patients:
- Suspicion of diagnosis or diagnosis of LHIPFOLD syndrome documented in the medical record, i.e. presence of these three manifestations: severe intrathecal deficiency in 5MTHF< 10 nmol/L, hyperproteinorachia > 1 g/L, and white matter abnormalities on cerebral MRI.
- Patient covered by Social Security or Complementary Health Insurance or any equivalent scheme (including AME).
- For Neurological Controls (NC) :
- No chronic pathology (notably no renal, cardiac, pulmonary or hepatic disease)
- Patients with one of the following neurological pathologies (confirmed diagnosis or strong suspicion), investigated in the course of routine clinical practice: Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, intracranial hypertension, normal pressure hydrocephalus, frontotemporal dementia.
- For Healthy Volunteers (VS):
- No chronic pathology (in particular, no renal, cardiac, pulmonary, hepatic or psychiatric disease)
- No history of neurological pathology
- No chronic alcohol intoxication
- No consumption of toxic substances in the week preceding the inclusion visit
- No neurological or psychotropic medication.
Exclusion Criteria11
- For all research participants:
- Age <18
- Pregnant and breast-feeding women.
- Participant unable to give informed consent.
- Participant with a contraindication to MRI: implantable cardiac defibrillators, prostheses, transdermal patches, catheters; implantable pumps; artificial heart valves; implants to treat deafness (if incompatible with MRI); surgical neurostimulator clips., pregnancy, extreme claustrophobia.
- Participants with contraindications to contrast injection: known allergy to gadolinium chelates, severe renal insufficiency, pregnancy (BHCG for women of childbearing age prior to MRI), breast-feeding.
- Participants with contraindications to LP: haemostasis abnormalities (PT<50%, platelets < 40*109/L), mass syndrome on brain imaging, suspected infection at or near the needle insertion site, coagulopathy, cardiopulmonary insufficiency or respiratory distress.
- For NC and VS :
- Participant under legal protection (guardianship, curatorship)
- Participant not covered by Social Security or Complementary Health Insurance or any equivalent scheme (excluding AME).
- Taking folate, vitamin C or dietary supplements containing vitamins (excluding vitamin D and E) in the two months prior to inclusion.
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Interventions
* blood sample * lumbar punction * MRI
Locations(2)
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NCT06403189