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

## TL;DR

This study finds that people with certain genetic variants linked to synuclein disorders show early psychiatric symptoms before being diagnosed with Parkinson's disease.

## Contribution

The study identifies neuropsychiatric symptoms as an early sign of synucleinopathy in pre-clinical GBA carriers.

## Key findings

- GBA carriers over 70 showed significantly increased neuropsychiatric symptoms compared to controls.
- Neuropsychiatric symptom severity was higher in the top quartile of GBA carriers compared to controls.
- No cognitive differences were observed between GBA carriers and non-carriers.

## Abstract

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.

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:
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.

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

This study examines neuropsychiatric symptoms in pre‐clinical carriers of GBA variantsGBA carriers over 70 years old show significantly more pre‐clinical neuropsychiatric symptoms, and carrier status is linked to severity of symptomsNeuropsychiatric 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

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