Objective: To investigate the clinical characteristics and predictive value associated with subjective cognitive decline (SCD) in people with Parkinson’s disease (PD) carrying pathogenic GBA or LRRK2 mutations versus sporadic PD.

Background: SCD, a self-perceived reduction in cognitive function with normal performance on standardised cognitive tests, is frequent and has been associated with potential subsequent cognitive decline in idiopathic PD (iPD)¹. GBA and LRRK2 mutations are known to play a role in cognitive function in PD², but the prevalence and prognostic significance of SCD in patients GBA-positive (GBA-PD) or LRRK2-positive (LRRK2-PD) have not been explored yet.

Method: Eighty GBA-PD, 148 LRRK2-PD patients and 394 iPD were included from the Parkinson’s Progression Markers Initiative (www.ppmi-info.org). Prevalence of normal cognition (NC), SCD, mild cognitive impairment (PD-MCI) and dementia (PDD) were assessed in each group. Baseline clinical and fluid biomarker data were compared across iPD-SCD, GBA-SCD and LRRK2-SCD groups. For each cohort (iPD, GBA, and LRRK2), the relationship between NC and SCD groups with longitudinal cognitive changes were assessed using linear mixed effects models (LMM).

Results: In the GBA-PD group, 68.8% of patients had NC, 13.8% had SCD, 13.8% were diagnosed with PD-MCI, while 3.8% had PDD. In the LRRK2-PD group, 77.7% of patients had NC, 11.5% had SCD while 10.1% and 0.7% had PD-MCI and PDD respectively. In the iPD group, the prevalence of cognitive syndromes was 79.7% (NC), 8.6% (SCD), 11.4% (MCI), and 0.3% (PDD). LRRK2-SCD patients had higher depression scores compared to GBA-SCD and iPD-SCD (p<0.01). GBA-SCD patients had lower CSF Aβ42 (p<0.05). Over 5-year follow up, only GBA-PD and LRRK2-PD groups showed to be significant predictors of objective decline on cognitive tests of memory, working memory and executive function. In the genetic cohorts, LMM-estimated decline in cognitive scores for the SCD appeared to be higher than those in the NC groups.

Conclusion: SCD occurs not only in iPD, but also in patients with GBA-PD and LRRK2-PD. SCD in LRRK2-PD is associated with higher depression scores and, in GBA-PD, with lower CSF Aβ42. In addition, the presence of SCD in patients with GBA and LRRK2 mutations may better signpost longitudinal objective decline in cognitive tests compared to genetic patients with no subjective cognitive complaints.

References: 1. Siciliano, M., Tessitore, A., Morgante, F., Goldman, J.G. and Ricciardi, L. (2024), Subjective Cognitive Complaints in Parkinson’s Disease: A Systematic Review and Meta-Analysis. Mov Disord, 39: 17-28. https://doi.org/10.1002/mds.29649
2. Aarsland, D., Batzu, L., Halliday, G. M., Geurtsen, G. J., Ballard, C., Ray Chaudhuri, K., & Weintraub, D. (2021). Parkinson disease-associated cognitive impairment. Nature reviews. Disease primers, 7(1), 47. https://doi.org/10.1038/s41572-021-00280-3

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MDS Abstracts - https://www.mdsabstracts.org/abstract/characterisation-and-longitudinal-significance-of-subjective-cognitive-decline-in-gba-and-lrrk2-parkinsons-disease/