Synuclein Disorder‐Related Genetic Determinants of Mild Behavioural Impairment in a Pre‐Clinical Community Cohort

Abstract

Background: The GBA variant confers increased risk of synuclein disorders but it is unclear what impact it has in pre-clinical groups. This study aimed to identify early psychiatric and cognitive manifestations amongst pre-clinical GBA carriers in a community cohort.

Method: This study used data from the PROTECT-UK cohort to compare 388 GBA carriers (N370S, E326K and T369M) without Parkinson's disease to age-matched controls. Neuropsychiatric symptoms (NPS) were measured with the Mild Behaviour Impairment Checklist, and cognition was measured using computerised neuropsychology.

Results: Results: GBA carriers over 70 had significantly increased NPS compared with controls (z = 2.13, p = 0.03). There was no difference between carriers and non-carriers in younger individuals but a sub-group comparison in the overall cohort showed that NPS were more severe in quartile four (Q4) of carriers compared to Q4 of controls (z = 2.39, p = 0.017), indicating an increase in NPS in this sub-group across a broader age range. No differences in cognition were seen.

Discussion: These findings suggest that NPS may be an early clinical manifestation of emerging synucleinopathy amongst individuals prior to diagnosis.

Key Points:

* This study examines neuropsychiatric symptoms in pre-clinical carriers of GBA variants

* GBA carriers over 70 years old show significantly more pre-clinical neuropsychiatric symptoms, and carrier status is linked to severity of symptoms

* Neuropsychiatric symptoms may be an early clinical manifestation of emerging synucleinopathy amongst pre-clinical carriers, raising the potential for early risk profiling based on genetic status