The Influence of GBA and LRRK2 on Mood Disorders in Parkinson's Disease

Abstract

BackgroundBackground: Mood disorders have emerged as major non-motor comorbidities in Parkinson's disease (PD) even at the prodromal stage of the disease. Mutations in the LRRK2 and GBA genes are common among Ashkenazi Jews, with more severe phenotype reported for GBA-PD. Objective Objective: To explore the association between genetic status and mood related disorders before and after diagnosis of PD and the association between mood-related medications, phenotype, and genetic status. Methods Methods: Participants were genotyped for mutations in the LRRK2 and GBA genes. State of depression, anxiety and non-motor features were evaluated using validated questionnaires. History of mood disorders prior to diagnosis of PD and use of mood-related medications were assessed. ResultsResults: The study included 105 idiopathic PD (iPD), 55 LRRK2-PD and 94 GBA-PD. Scores on mood related questionnaires and frequency of depression and anxiety before diagnosis were similar between the groups (p>0.05). However, more GBA-PD patients used mood related medications before PD diagnosis than LRRK2-PD and iPD (16.5% vs 7.1% and 8.2%, p=0.044). LRRK2-PD and GBA-PD receiving mood-related medications at time of assessment had worse motor and non-motor phenotype compared to those that did not (p<0.05). LRRK2-PD receiving mood related-medications at time of assessment, scored higher on mood-related questionnaires compared to LRRK2-PD not receiving such medications (p<0.04). Conclusions Conclusions: Prodromal GBA-PD are more frequently treated with mood related-medications despite equal rates of reported mood-related disorders, while LRRK2-PD with mood-related disorders experience high rates of anxiety and depression despite treatment, attesting to the need of more precise assessment and treatment of these genetic subgroups.Mood disorders such as depression and anxiety are common conditions in Parkinson's disease (PD) impacting patient outcomes. Recent studies estimate that 35% of PD patients will have clinically significant depression, a percentage which likely underestimates the underreported and underdiagnosed condition in PD. 1,2 Dopaminergic, serotonergic and adrenergic system changes have all been implicated in the development of concurrent mood disorders in PD 1,2 even at the prodromal stage of the disease, likely due to involvement of their respective nuclei (substantia nigra, raphe nuclei and locus coeruleus). 3 In addition to PD related medications (MAO B inhibitors, amantadine, dopamine agonists and L-DOPA), treatment options for depression and anxiety in PD are similar to those provided to patients without neurodegenerative conditions. 4 Standard pharmacologic treatment with antidepressants such as Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs), and Tricyclic Antidepressants (TCAs) has shown some success in PD. 5 In addition, PD related medication such as dopamine agonists and amantadine have antidepressive properties.

Longitudinal faster anxiety progression of GBA variant carriers in the early Parkinson’s disease cohort

“…Previous studies assessing anxiety in GBA-associated PD were mostly cross-sectional studies, and GBA variant carriers presented with a high prevalence of anxiety ( DeBroff et al, 2023 ). A few studies using univariable Kaplan–Meier survival analysis demonstrated that the GBA-PD group developed anxiety earlier than the idiopathic PD group ( Pachi et al, 2021 ).…”

“…Taking advantage of this longitudinal data from a well-designed cohort, our linear mixed model and multivariable Cox regression model showed that GBA variant carriers experienced more than 57% greater annual increase in STAI total anxiety score and faster progression in anxiety compared with non-carriers. Previous studies assessing anxiety in GBA-associated PD were mostly cross-sectional studies, and GBA variant carriers presented with a high prevalence of anxiety (DeBroff et al, 2023). A few studies using univariable Kaplan-Meier survival analysis demonstrated that the GBA-PD group developed anxiety earlier than the idiopathic PD group (Pachi et al, 2021).…”

Parkinson’s LRRK2-G2019S risk gene mutation drives sex-specific behavioral and cellular adaptations to chronic variable stress

“…In idiopathic Parkinson’s, symptoms of anxiety and depression are more prevalent in women than in men (Leentjens et al, 2011; Cui et al, 2017). Although the prevalence of anxiety and depression in human LRRK2 mutation carriers is similar to that in idiopathic Parkinson’s (Gaig et al, 2014; San Luciano et al, 2017; Chen et al, 2020b; DeBroff et al, 2023), it is less clear whether there are sex differences in psychiatric symptoms among manifesting LRRK2 G2019S carriers. One study suggests that depression severity may be similar in male and female mutation carriers (San Luciano et al, 2017), which aligns with the equal penetrance of the mutation in male and female carriers (Marder et al, 2015).…”

“…The G2019S mutation in LRRK2 (encoding leucine-rich repeat kinase 2) is among the most common genetic risk mutations for familial and sporadic Parkinson’s (Kluss et al, 2019). LRRK2 G2019S produces late-onset Parkinson’s that is clinically similar to idiopathic forms, including prodromal anxiety and depression in non-manifesting mutation carriers (Shanker et al, 2011; DeBroff et al, 2023). Genetic, pathological, and preclinical studies suggest that dysregulated LRRK2 may be part of a common pathological mechanism (Kluss et al, 2019; Rocha et al, 2022; Peter and Strober, 2023).…”

Pharmacological and Non-Pharmacological Treatments for Depression in Parkinson’s Disease: An Updated Review

“…Furthermore, despite therapeutic intervention, PD patients with LRRK2 gene mutations and mood disorders have considerably high depression and anxiety rates. PD patients with mood-related disorders experience high rates of anxiety and depression [ 160 ]. In this context, clinical vigilance for depression screening for patients known to carry these mutations is needed.…”