Deep Cerebral Folate Deficiency as a clinical model for identification of MRI and biochemical signatures of Choroid Plexus dysfunction – PLEXFOLD

Cerebral folate deficiency (CFD), 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, and be associated to potentially very disabling cognitive and motor symptoms. We identified a neurological syndrome (named LHIPFOLD for Leukoencephalopathy with High CSF Protein and FOLate Deficiency) characterized by deep CFD with normal blood folate, high protein level in CSF (>1g/L) and a specific leukoencephalopathy. A folate supplementation may stabilize or even improve symptoms in some patients, but with limited impact. In some patients, this syndrome is associated to genetic mutations leading to a mitochondrial malfunction, without connection to folate metabolism, whereas LHIPFOLD syndrome remains unexplained in others even after genome sequencing. We hypothesize that CFD in LHIPFOLD is due to generalized 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 in CSF with various functions (trophic function, adult neurogenesis, etc). Consequently, other potentially treatable biochemical abnormalities due to PC dysfunction may exist in LHIPFOLD, beyond CFD. Currently, there are no available clinical explorations to evaluate CP functions, whereas we consider LHIPFOLD a very useful model to validate the capacity of some relevant diagnostic tools to do so. Therefore, our 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 blood/CSF metabolomics/proteomics approaches (untargeted then targeted validation of candidate biomarkers related to CP physiology); to identify CP-related biochemical therapeutic targets in LHIPFOLD patients that could improve patients condition combined to folate supplementation; and to set-up imaging and biochemical diagnostic tests investigating CP function for clinical practice. For this, brain MRI data and blood/CSF samples will be collected during 2 years from LHIPFOLD patients and controls (healthy volunteers and neurological patients). 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 or multiple sclerosis. Therefore, efficient diagnostic tools exploring CP function will be of great utility not only in suspected LHIPFOLD patients but also in more common neurological diseases, potentially leading to original therapeutic approaches.