Friday, May 9, 2025
5/9/2025
Cerebrospinal fluid dynamics in Huntington's disease - PROJECT SUMMARY The overall objective of this work is to apply innovative neuroimaging methods of cerebrospinal fluid (CSF) production, transport, and resorption in patients with Huntington’s disease (HD) to test fundamental hypotheses regarding the sequelae of aberrant neurofluid circulation in HD participants. New intrathecally administered ASOs have gained great interest as a disease-modifying treatment in HD, and yet in HD, these interventions have resulted in increases in neurofilament light protein (NfL) levels, and greater ventricular volumes. Importantly, post-hoc data indicates some may benefit from these interventions, and new trials are being developed. Heterogeneity in treatment response may be explained by CSF flow dysfunction. The recent proposal of the glial-lymphatic system has highlighted the importance of neurofluid circulations. For instance, the current paradigm describes CSF circulation as a combination of perivascular, interstitial, and bulk flow pathways. The CSF is produced by the choroid plexus (ChP) complexes, traverses the brain parenchyma along peri-arterial and peri-venous pathways, and exits the brain along parasagittal dural (PSD) space, cranial nerves and through dural venous sinuses. We have established a collaborative effort between neurologists, imaging scientists, and neuroradiologists to investigate quantitative changes in neurofluid circulation in the setting of neurodegeneration. These investigations provide a more comprehensive perspective on neurofluid production and flow and allow for sequential assessments of choroid plexus (ChP) perfusion, CSF flow and velocity, and volumetric assessments of the parasagittal dural space (PSD), with established relevance in neurofluid egress. Using these approaches, we have characterized age-related declines in ChP perfusion and net CSF flow, and increases in ChP and PSD volume, across the healthy lifespan in 80 healthy adults, demonstrated that a subset of these markers including PSD hypertrophy directly correlate with proteinopathy extent in 24 older adults with neurodegenerative proteinopathies, and, in preliminary data motivating this project, that these same trends persist in 29 patients progressing from pre-manifest to manifest stages of HD on a more accelerated timescale. We propose to apply these methods for the first time to characterize the range of neurofluid aberrations more fully across HD stages; to differentiate choroid plexus pathology, characterize CSF movement through the cerebral aqueduct and brain cisterns, and peri-sinus space anatomy with the quantification of PSD across HD stages. Data collected during this project are intended to further inform our understanding of HD pathophysiology and provide biomarker ranges that will be required to rigorously inform a future trial based on personalized signatures of hypothesized responsiveness.
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