AUTHOR=Pavelka Lukas , Rawal Rajesh , Sapienza Stefano , Klucken Jochen , Pauly Claire , Satagopam Venkata , Krüger Rejko 

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

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=16

YEAR=2024

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2024.1479572

DOI=10.3389/fnagi.2024.1479572

ISSN=1663-4365

ABSTRACT=<sec id="sec1"><title>Background</title><p>Freezing of gait (FOG) is an important milestone in the individual disease trajectory of people with Parkinson’s disease (PD). Based on the <italic>cognitive model</italic> of FOG etiology, the mechanism behind FOG implies higher executive dysfunction in PD<sup>FOG+</sup>. 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.</p></sec><sec id="sec2"><title>Methods</title><p>A cross-sectional analysis comparing iPD<sup>FOG+</sup> (<italic>n</italic> = 118) and iPD<sup>FOG−</sup> (<italic>n</italic> = 378) individuals was performed, followed by the application of logistic regression models. Consequently, regression models were fitted for a subset of iPD<sup>FOG+</sup> (<italic>n</italic> = 35) vs. iPD<sup>FOG−</sup> (<italic>n</italic> = 126), utilizing a detailed neuropsychological battery to assess the association between FOG and cognitive subdomains. Both regression models were adjusted for sociodemographic confounders and disease severity.</p></sec><sec id="sec3"><title>Results</title><p>iPD<sup>FOG+</sup> individuals presented with more motor complications (MDS-UPDRS IV) compared to iPD<sup>FOG-</sup> individuals. Moreover, iPD<sup>FOG+</sup> individuals exhibited a higher non-motor burden, including a higher frequency of hallucinations, higher MDS-UPDRS I scores, and more pronounced autonomic dysfunction as measured by the SCOPA-AUT. In addition, iPD<sup>FOG+</sup> individuals showed lower sleep quality along with lower quality of life (measured by PDSS and PDQ-39, respectively). The cognitive subdomain analysis in iPD<sup>FOG+</sup> vs. iPD<sup>FOG−</sup> 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.</p></sec><sec id="sec4"><title>Conclusion</title><p>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 PD<sup>FOG+</sup> with additional higher impairment in visuospatial function and memory encoding.</p></sec>