Genetically stratified Parkinson’s disease with freezing of gait is related to specific pattern of cognitive impairment and non-motor dominant endophenotype#

Authors#

Lukas Pavelka, Rajesh Rawal, Stefano Sapienza, Jochen Klucken, Claire Pauly, Venkata Pardhasaradhi Satagopam, Rejko Krüger on behalf of the NCER-PD Consortium

Abstract#

Background:#

Freezing of gait (FOG) is an important milestone in the individual disease trajectory of people with Parkinson’s disease (PD). Based on the cognitive model of FOG aetiology, the mechanism behind FOG implies higher executive dysfunction in PDFOG+. To test this model, we investigated the FOG-related phenotype and cognitive subdomains in idiopathic PD (iPD) patients without genetic variants linked to PD from the Luxembourg Parkinson’s study.

Methods:#

Cross-sectional analysis of iPDFOG+ (n=118) vs. iPDFOG- (n=378) was performed followed by logistic regression models. Consequently, regression models were fitted in a sub-set of iPDFOG+ (n=35) vs. iPDFOG- (n=126) with detailed neuropsychological battery to assess the association of FOG with cognitive subdomains. Both regression models were adjusted for sociodemographic confounders and disease severity.

Results:#

iPDFOG+ presented with more motor complications (MDS-UPDRS IV) compared to iPDFOG-. Moreover, higher non-motor burden was observed in iPDFOG+, i.e. higher frequency of hallucinations, higher MDS-UPDRS I score and more pronounced autonomic dysfunction (measured by SCOPA-AUT). Additionally, iPDFOG+ showed lower sleep quality along with lower quality of life (measured by PDSS and PDQ-39 respectively). The cognitive subdomain analysis in iPDFOG+ vs. iPDFOG- indicated lower scores in Benton’s Judgment of Line Orientation test and CERAD word recognition reflecting higher impairment in visuospatial, executive function and memory encoding.

Conclusions:#

We determined a significant association between FOG and a clinical endophenotype of PD with higher non-motor burden. While our results supported the cognitive model of FOG, our findings point to a more widespread cortical impairment across cognitive subdomains beyond the executive domain in PDFOG+ with additional higher impairment in visuospatial function and memory encoding.