Cerebrospinal Fluid Flow in Patients with Huntington's Disease

Abstract

ObjectiveInvestigations of cerebrospinal fluid (CSF) flow aberrations in Huntington's disease (HD) are of growing interest, as impaired CSF flow may contribute to mutant Huntington retention and observed heterogeneous responsiveness to intrathecally administered therapies.MethodWe assessed net cerebral aqueduct CSF flow and velocity in 29 HD participants (17 premanifest and 12 manifest) and 51 age‐ and sex matched non‐HD control participants using 3‐Tesla magnetic resonance imaging methods. Regression models were applied to test hypotheses regarding: (i) net CSF flow and cohort, (ii) net CSF flow and disease severity (CAP‐score), and (iii) CSF volume after correcting for age and sex.ResultsGroup‐wise analyses support a decrease in net CSF flow in HD (mean 0.14 ± 0.27 mL/min) relative to control (mean 0.32 ± 0.20 mL/min) participants (p = 0.02), with lowest flow in the manifest HD cohort (mean 0.04 ± 0.25 mL/min). This finding was explained by hyperdynamic CSF movement, manifesting as higher caudal systolic CSF flow velocity and higher diastolic cranial CSF flow velocity across the cardiac cycle, in HD (caudal flow: 0.17 ± 0.07 mL/s, cranial flow: 0.14 ± 0.08 mL/s) compared to control (caudal flow: 0.13 ± 0.06 mL/s, cranial flow: 0.11 ± 0.04 mL/s) participants. A positive correlation between cranial diastolic flow and disease severity was observed (p = 0.02).InterpretationsFindings support aqueductal CSF flow dynamics changing with disease severity in HD. These accelerated changes are consistent with changes observed over the typical adult lifespan, and may have relevance to mutant Huntington retention and intrathecally administered therapeutics responsiveness. ANN NEUROL 2023

NfL concentration in CSF is a quantitative marker of the rate of neurodegeneration in aging and Huntington's disease: a semi-mechanistic model-based analysis

“…The current gold standard for quantifying CSF production is regarded to be the MRI-based measurement of net CSF flow rate through the cerebral aqueduct (Liu et al, 2022 ). Using this technique, Hett et al ( 2023 ) recently reported the median values of the net CSF flow rate to be 303 μL/min in healthy controls (mean age 46.6 yr; CAG < 37), 136 μL/min in premanifest HD subjects (mean age 41.5 yr; mean CAG 42) and 108 μL/min in manifest HD subjects (mean age 45.9 yr; mean CAG 45). Given the consistency of the healthy control value with the normative data summarized above, we have taken the three median values from Hett's study as fixed parameter estimates of the CL NfL values for the respective groups in our model.…”

“…We have developed a novel quantitative, semi-mechanistic model of the dynamics of NfL concentrations in CSF and its relationship to neurodegeneration, based on an analysis of data from healthy controls and HD subjects in the HD-CSF study (Rodrigues et al, 2020 ). Our principal findings are that the NfL concentration in CSF is directly proportional to the rate, rather than the extent, of neurodegeneration (defined as the negative rate of change of whole brain volume) and is inversely proportional to the flow rate of CSF, which is reduced in HD subjects relative to healthy subjects (Hett et al, 2023 ). The linear increase of the NfL concentration in CSF with age (or time), observed in both healthy controls and HD subjects, is explained in our model by the acceleration of the neurodegeneration rate, which is quantified by modeling the time-course of brain volume with a 2nd order polynomial, i.e., a quadratic dependence.…”

“…The adjusted total brain volume was computed as the ratio of whole brain volume-to-TIV, multiplied by the mean TIV of the population (personal communication from R. Scahill). The median net CSF flow rates (μL/min) for healthy controls ( n = 51), premanifest HD ( n = 17) and manifest HD ( n = 12) measured by MRI methods were obtained from a separate study (Hett et al, 2023 ).…”

“…The HD-CSF study was approved by the London Camberwell St. Giles Research Ethics Committee (15/LO/1917). The Hett et al ( 2023 ) study was approved by an unnamed local institutional review board. The Sjölin et al ( 2022 ) study analyzed post-mortem brain samples obtained from the Karolinska Institute's tissue donation program.…”

“…Here, we characterize the quantitative relationships between MRI measurements of whole brain volume, NfL concentration in CSF, and measurements of CSF flow rates in healthy controls and HD subjects using published data from the HD-CSF study (Rodrigues et al, 2020 ) and a separate study of CSF flow (Hett et al, 2023 ). Based on mass-balance principles, we derive a novel, semi-mechanistic model that relates the NfL concentration in CSF to the rate of change of whole brain volume, the respective CSF flow rates, and the estimated NfL concentration in brain tissue.…”