Abstract
Multiple targeted therapeutics for Huntington's disease are now in clinical trials, including intrathecally delivered compounds. Previous research suggests that CSF dynamics may be altered in Huntington's disease, which could be of paramount relevance to intrathecal drug delivery to the brain. To test this hypothesis, we conducted a prospective cross‐sectional study comparing people with early stage Huntington's disease with age‐ and gender‐matched healthy controls. CSF peak velocity, mean velocity and mean flow at the level of the cerebral aqueduct, and sub‐arachnoid space in the upper and lower spine, were quantified using phase contrast MRI. We calculated Spearman's rank correlations, and tested inter‐group differences with Wilcoxon rank‐sum test. Ten people with early Huntington's disease, and 10 controls were included. None of the quantified measures was associated with potential modifiers of CSF dynamics (demographics, osmolality, and brain volumes), or by known modifiers of Huntington's disease (age and HTT CAG repeat length); and no significant differences were found between the two studied groups. While external validation is required, the attained results are sufficient to conclude tentatively that a clinically relevant alteration of CSF dynamics – that is, one that would justify dose‐adjustments of intrathecal drugs – is unlikely to exist in Huntington's disease.
Highlights
Huntington's disease is a fatal, incurable inherited neurodegenerative disorder
It is important to understand whether the delivery of intrathecally administered substances to the brain may be altered by disease-related variations in cerebrospinal fluid (CSF) flow
We studied the effect of age, gender, serum osmolality, and brain volumes
Summary
Huntington's disease is a fatal, incurable inherited neurodegenerative disorder. Caused by a CAG (cytosine- adenine-guanine)-triplet repeat expansion in the HTT gene, symptoms usually begin in mid-adulthood, and include motor, cognitive, and psychiatric disturbances (Bates et al, 2015; Rodrigues et al, 2017). In the subarachnoid space throughout the neuraxis, cerebrospinal fluid (CSF) has a pulsatile to and fro movement, with local exchanges happening among CSF, interstitial fluid, and blood (Brinker, Stopa, Morrison, & Klinge, 2014) This oscillation can be used for drug delivery from the spinal intrathecal space to the brain. A case report of atypical performance of spinal anaesthesia in an Huntington's disease patient (Draisci et al, 2012) raises the suspicion that these Huntington's disease-related changes may together produce clinically relevant alterations of CSF dynamics This could have important consequences for the distribution of central nervous system (CNS)-delivered drugs, meriting consideration in the planning of clinical trial regimens. Using PCMRI gated to the cardiac cycle, it is possible to noninvasively measure the dynamics of moving biofluids, CSF, and quantify velocity and flow rates
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