D018 Multimodal analysis of mutant Huntingtin, NfL, and MRI correlations in Huntington's disease

<h3>Objective</h3> This study aims to investigate correlations between mHtt and NfL levels and MRI findings in individuals at different stages of HD, including presymptomatic and symptomatic individuals. <h3>Background</h3> Biomarkers in Huntington9s disease (HD) are crucial for understanding disease progression and developing effective therapies. Cerebrospinal fluid (CSF) biomarkers like neurofilament light chain (NfL) are sensitive indicators of neurodegeneration, while mutant Huntingtin (mHtt) is specific to HD. Magnetic resonance imaging (MRI) provides detailed insights into brain structure and neurodegenerative changes. However, there is a lack of studies using multimodal techniques to correlate neurodegeneration in specific brain structures with CSF biomarkers. <h3>Methods</h3> Longitudinal study with cross-sectional analysis of a cohort of individuals with genetic confirmation of Huntington9s disease (HD) and controls. Participants were grouped into presymptomatic (preHD) at the motor level (DLC&lt;4) and symptomatic (HD) (DCL=4). Levels of NfL in CSF were quantified using the Simoa platform (Quanterix), and mHTT levels in CSF were measured using the SMC Erenna platform (Merck). MRI scans were performed using a 3 Tesla machine, with gray matter analysis conducted via VBM and cortical thickness assessed using FreeSurfer. Correlations between NfL and mHtt biomarkers and neuroimaging findings were established using SPM. <h3>Results</h3> Sixty-one participants, comprising 27 presymptomatic, 24 symptomatic, and 10 controls, demonstrated age differences between groups (age covaried). Presymptomatic individuals exhibited elevated levels of NfL and mHtt compared to controls, with further increases observed in symptomatic individuals. NfL levels correlated significantly with caudate, putamen, and cerebellar atrophy in presymptomatics (p&lt;0.005), while mHtt levels showed weaker correlation (p&lt;0.05). In symptomatic individuals, NfL levels correlated with thalamic, posterior cortical, and prefrontal atrophy, whereas mHtt levels correlated less strongly with posterior cortical atrophy, suggesting that NfL may offer higher sensitivity in detecting neurodegeneration and/or involvement of non-Huntingtin-dependent processes. <h3>Conclusion</h3> In summary, NfL levels show heightened sensitivity in detecting the neurodegenerative process compared to mHtt, as evidenced by their correlation with atrophy in the caudate and putamen in presymptomatic individuals. This correlation extends to cortical areas as the disease progresses.