Hett, Kilian; Dubois, Abigail R.; Leguizamon, Melanie; Song, Alexander K.; Trujillo, Paula; McKnight, Colin David; Considine, Ciaran Michael; Donahue, Manus Joseph; & Claassen, Daniel O. (2026). Functional and structural evidence of neurofluid circuit aberrations in Huntington disease. Annals of Clinical and Translational Neurology. Advance online publication. https://doi.org/10.1002/acn3.70328
Disruptions in the brain’s fluid systems may contribute to the nerve cell damage seen in Huntington disease (HD). These fluid pathways are important for clearing waste, controlling inflammation, and distributing treatments delivered to the brain. In this study, we examined two key components of this system: the choroid plexus (ChP), which produces cerebrospinal fluid (CSF), and the parasagittal dural (PSD) space, a major CSF drainage pathway. We measured their size and function using advanced MRI techniques and analyzed how these measures relate to disease severity and genetic risk.
We studied 80 people with HD and 65 healthy controls. Compared with controls, people with HD had larger ChP and PSD structures and reduced blood flow through the ChP. Individuals with greater genetic risk (larger CAG repeat expansions) showed the largest changes, and these differences were linked to worse motor symptoms.
These results show that HD affects both the structure and function of key brain fluid pathways. Understanding these changes may help explain disease mechanisms and improve the delivery of treatments that rely on cerebrospinal fluid, highlighting the need for further research.
FIGURE 1
Cerebrospinal fluid (CSF) production and flow shown (A) schematically and on (B) axial, (C) sagittal, and (D) coronal T2-weighted MRI: (A) The bulk CSF flow pathway consists of (B) CSF production in the choroid plexus (ChP) complexes (yellow arrows), (C) flow through the cerebral aqueduct (orange arrow) at a typical peak velocity of 5–15 cm/s, outflow from the ventricular system via the foramina of Luschka and Magendie, circulation of the cerebrum and subarachnoid space, and uptake into the venous system via arachnoid granulations. Recent reports also suggest that CSF egress can occur (D) along conduits within the peri-sinus parasagittal dural space (green arrows).