A Two-Track Model of Striatal Degeneration in Huntington’s Disease: Independent Contributions of Cytoskeletal Damage and Immune Dysregulation Consistent with an Immune-Exhaustion-Like Profile

Huntington’s disease (HD) is characterized by progressive striatal atrophy and complex proteomic changes in the central nervous system. Using the ultrasensitive NULISA proteomic platform, we analyzed cerebrospinal fluid (CSF) from 88 persons with HD to dissect the biological correlates of gray matter loss. We identified a two-signal pattern of pathology. The first track, marked by the axonal damage protein Neurofilament Light (NEFL), showed a strong negative correlation with putamen volume (Pearson r = -0.53, p < 0.001), consistent with prior work supporting NEFL as a proxy for neurodegeneration and brain atrophy in HD. The second track was defined by a positive association between the immune regulator TNFRSF8 (CD30) and putamen volume (Pearson r = 0.36, p < 0.001), indicating a loss of putative immune-regulatory signal as atrophy progresses. TNFRSF8 was pre-specified for follow-up given its immune-regulatory role and interpretability in the context of immune dysregulation consistent with an immune-exhaustion-like profile. TNFRSF8 showed an independent association with striatal volume (Beta = 0.24, p = 0.008) after controlling for NEFL, CAG-Age-Product (CAP) score, and sex. These findings suggest that reduced immune-regulatory signaling is a distinct pathological correlate in HD, separable from general cytoskeletal damage, and warrants evaluation in longitudinal and interventional studies.