Pyramidal signs in Huntington's disease: An early clinical indicator associated with proximity to disease onset.

BACKGROUND

Previous studies in Huntington's disease (HD) have primarily focused on striatal degeneration, while pyramidal signs remain insufficiently characterized. Understanding the clinical significance of pyramidal signs in HD is crucial for elucidating the disease's pathogenesis.

METHODS

In a cross-sectional cohort, 29 individuals with premanifest HD (pre-HD) and 196 patients with manifest HD underwent standardized neurological examination. Serum neurofilament light-chain (sNfL) levels, clinical assessments, and MRI were obtained. In addition, a prospective longitudinal cohort including 15 individuals with pre-HD and 51 patients with manifest HD was followed up.

FINDINGS: In the cross-sectional cohort, the prevalence of pyramidal signs was 44.8% in individuals with pre-HD and 63.3% in patients with manifest HD. Individuals with pre-HD with pyramidal signs exhibited significantly higher sNfL levels (17.4 vs. 9.3 pg/mL, p = 0.0010) and were closer to predicted motor onset (p = 0.0005) compared with those without pyramidal signs. In the longitudinal analysis, linear mixed-effects models revealed that the rates of disease progression did not differ significantly between pyramidal-sign-positive and -negative patients with manifest HD. Cox regression analysis further indicated that pyramidal signs emerged approximately 13.3 years before the predicted motor onset, in a manner dependent on CAG repeat length.

CONCLUSIONS

The presence of pyramidal signs in pre-HD reflects closer proximity to disease onset, but it lacks prognostic value in manifest HD. These signs typically emerge more than a decade before motor symptom onset and serve as a simple and predictive marker for physicians.

FUNDING: This study was supported by the National Natural Science Foundation of China to Z.-Y.W. (82230062, Beijing).