ABSTRACT
Background
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
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
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.
Results
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
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.
Keywords: Parkinson's disease, LRRK2, GBA, depression, anxiety
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 anti‐depressive properties. 6 , 7 , 8 A meta‐analysis of antidepressant use in PD patients concluded in part that an aggregate treatment of antidepressants had the most impact on depression in PD patients, and further noted that SSRIs on their own showed the most benefit. 9 In terms of anxiety treatment, benzodiazepines and SSRIs have been reported as effective for treatment of PD patients. 10
Mutations in the LRRK2 and GBA genes are the most common genetic contributors to the pathogenesis of PD. 11 GBA codes for the lysosomal enzyme β‐glucocerebrosidase that, if dysfunctional, affects the degradation of alpha‐synuclein and can ultimately lead to Lewy body formation and risk for earlier onset of PD. 12 Gain of function mutations in LRRK2 have been associated with a variety of pathological mechanisms including synaptic dysfunction and alternations of lysosomal trafficking. 13 Phenotypic studies in PD mutation carriers show that GBA‐PD have greater phenotypic burden compared to LRRK2‐PD. 11 , 14 , 15 , 16 Patients carrying GBA mutations have been shown to have an increased prevalence of neuropsychiatric disorders including depression compared to idiopathic PD (iPD) patients. 14 Depression frequency estimations in LRRK2‐PD vary between 30%‐65%. 17 , 18 With elevated rates of anxiety observed in this group. 19 Recent studies postulate that LRRK2's ability to regulate the downstream pathway of glucocerebrosidase, may play a role in its altered motor and non‐motor outcomes among PD patients. 20 Moreover, increased serotonin receptor binding was observed in LRRK2 carriers, underscoring another potential connection between PD associated mutations and mood disorders. 21
In this study, we aimed to explore the association between genetic susceptibility and mood. We evaluated the prevalence of mood disorders prior to diagnosis of PD in a population that carry mutations in the LRRK2 or GBA genes compared to iPD patients. Prodromal features as well as mood disorders after diagnosis were compared across genotypes. We hypothesized that GBA‐PD would show higher prevalence and severity of mood disorders in the years prior to diagnosis with worse phenotypic outcomes after PD diagnosis as compared with LRRK2‐PD and iPD. We further hypothesized that patients suffering from depression and anxiety would show worse PD phenotype compared to those reporting no mood related disorders.
Methods
This study evaluated cross‐sectional data from subjects who participated in the BEAT‐PD study (TLV‐0204‐16), a natural history study which set out to characterize LRRK2 and GBA‐PD. Patients were recruited if they were of Ashkenazi Jewish descent, diagnosed with PD by a movement disorders specialist based on the MDS criteria 22 and were at Hoehn and Yahr stages 1‐2. Exclusion criteria included additional neurological or previous psychotic disorders, active malignancy, or a diagnosis of HIV, Hepatitis B or C. The study was approved by the local ethical committee of the Tel‐Aviv Medical Center according to the guidelines of the Helsinki declaration. All participants received genetic counseling and provided an informed written consent prior to participation.
Procedure
Participants were genotyped for the G2019S‐LRRK2 mutation and 9 common mutations in the GBA gene; N370S, R496H considered mild mutations (mGBA‐PD), L444P, 84GG, IVS2+1G‐>A, V394L, 370Rec mutation, considered severe GBA mutations (sGBA‐PD), E326K and T369M, considered risk variants and the. 23 These mutations account for over 96% of the mutant alleles among Ashkenazi Jews. 24 Only heterozygote carriers were included in this study while subjects with dual mutation (LRRK2+GBA) and homozygote carriers were excluded due to their small sample size. Patients with no detectable mutations were considered iPD.
Information on existence of depression and anxiety prior to diagnosis of PD was obtained by a Movement Disorders Specialist using a structured interview, which assessed previous diagnosis of depression, anxiety and additional psychiatric conditions (bipolar disorder, panic attacks, specific phobias etc.). 25 Information on duration of symptoms and their severity were recorded. The use of medication to relieve symptoms including type, dose and duration of medication intake were obtained from the patients. The participants' signs and symptoms at the time of assessment were also evaluated. Disease severity was assessed using the MDS‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) during self‐report ON medication (approximately one hour after medication intake). The Montreal Cognitive Assessment (MoCA) was used to determine global cognitive functions; depression was assessed using the Beck Depression Inventory (BDI) and the Geriatric Depression Scale‐15 (GDS‐15). Cut‐off's of either 22 in the BDI or 7 for GDS‐15 were considered for depression. 26 Anxiety was assessed using the State‐Trait Anxiety Inventory (STAI) with a cut off of 40 used to define probable clinical levels of anxiety. 27 The Non‐Motor Symptoms Questionnaire (NMSQ), the Scale of Autonomic Function in PD (SCOPA‐AUT) as well as the REM sleep Behavior Disorder Questionnaire (RBDQ) were collected. RBD was defined as a score of 6 or above on the RBDQ. A full medication list was obtained and Levodopa equivalent daily dose (LEDD) 28 was calculated for all patients. Anti‐depressive and anti‐anxiolytic medications (SSRI, SNRI, tricyclic antidepressants (TCA) and benzodiazepines) were marked and grouped as mood related medications together with Amantadine and dopamine agonists. History of falls in the 6 months prior to the study was obtained based on recall to explore relation to medication intake.
Statistical analysis
Descriptive statistics (means and standard deviations (SD)) were computed for all measures. Data was assessed for normal distribution using box plots. Linear Regression Models were used to assess differences between groups with genetic status as the fixed factor and LEDD and age as covariates. Differences in categorical measures (e.g., sex and the occurrence of depression before PD diagnosis) were evaluated using chi square tests (χ 2). Significance was determined at p<0.05 and as this was an exploratory study, results were not corrected for multiplicity. Statistical analysis was performed using SPSS version 22.
Results
A total of 254 patients with PD were included in this study; 105 iPD; 55 LRRK2 PD and 94 GBA‐PD (67 mild GBA‐PD, 17 severe GBA‐PD and 10 risk variant GBA‐PD). Our data was not powered to compare behavioral measures between the different GBA subgroups; therefore, they were considered one group.
At the time of assessment, groups had similar characteristics, frequency and severity of most motor and non‐motor symptoms (Table 1). LEDD significantly differed between the three groups with a post‐hoc analysis demonstrating that GBA‐PD received higher LEDD than iPD (p=0.005). A trend for between group difference in total MDS‐UPDRS scores was detected, with LRRK2‐PD having lower scores compared with GBA‐PD (p=0.006) and iPD (p=0.081). The groups were similar in anxiety and depression scores (p>0.05). None of the cohort reported bipolar disorder, panic attacks or specific phobias.
TABLE 1.
Patient demographics and clinical features of study cohort. Findings are reported as mean ± SD (range)
| Characteristic | IPD (N=105) | LRRK2‐PD (N=55) | GBA‐PD (N=94) | p value |
|---|---|---|---|---|
| N370S – 62 | ||||
| E326k – 6 | ||||
| 84GG – 5 | ||||
| R496H – 5 | ||||
| Rec370 – 4 | ||||
| T369M – 4 | ||||
| IVS2+1 – 4 | ||||
| V394L – 3 | ||||
| L444P – 1 | ||||
| Age (y) |
66.42 ± 10.48 (36‐87) |
65.2 ± 10.60 (34‐82) |
65.24 ± 9.28 (42‐86) |
0.647 |
| Sex (M/F) | 72/33 | 32/23 | 62/32 | 0.550 |
| Disease duration (y) |
2.51 ± 1.93 (1‐7) |
2.93 ± 2.55 (1‐9) |
3.2 ± 2.68 (0‐10) |
0.116 |
| MOCA score |
23.99 ± 3.69 (18‐30) |
24.22 ± 4.14 (18‐30) |
23.45 ± 4.01 (18‐30) |
0.443 |
| RBDQ |
2.99 ± 2.52 (0‐11) |
2.78 ± 2.21 (0‐10) |
3.63 ± 3.33 (0‐12) |
0.157 |
| Participants with RBD (n, %) | 17 (16%) | 6 (11%) | 23 (26.1%) | 0.087 |
| NMSQ |
7.40 ± 4.65 (0‐20) |
6.52 ± 3.63 (0‐13) |
7.71 ± 5.14 (0‐21) |
0.346 |
| SCOPA‐AUT |
16.80 ± 10.14 (1‐44) |
17.00 ± 10.91 (4‐56) |
15.96 ± 10.43 (1‐51) |
0.823 |
| LEDD (mg) |
274.33 ± 277.83 (0‐1200) |
372.02 ± 368.76 (0‐1358) |
394.01 ± 393.10 (0‐1832) |
0.037 |
| MDS‐UPDRS III |
22.86 ± 11.72 (7‐84) |
19.65 ± 8.78 (7‐43) |
23.57 ± 11.99 (8‐81) |
0.108 |
| MDS‐UPDRS T |
38.15 ± 17.97 (9‐121) |
32.73 ± 15.07 (11‐81) |
39.85 ± 19.80 (8‐129) |
0.063 |
| BDI score |
7.85 ± 6.16 (0‐32) |
8.08 ± 7.79 (0‐44) |
8.91 ± 7.62 (0‐35) |
0.570 |
| GDS score |
3.43 ± 2.83 (0‐12) |
3.44 ± 3.30 (0‐14) |
3.50 ± 3.12 (0‐15) |
0.987 |
| STAI‐S score |
52.27 ± 5.55 (32‐68) |
52.7 ± 5.43 (33‐65) |
51.31 ± 5.54 (35‐68) |
0.303 |
| STAI‐T score |
55.11 ± 5.45 (31‐70) |
54.42 ± 4.75 (40‐70) |
54.88 ± 4.51 (30‐70) |
0.726 |
| Participants presenting depression (n,%) | 50 (47.6%) | 25 (45.5%) | 49 (50%) | 0.207 |
| Participants presenting anxiety (n, %) | 86 (81%) | 48 (87%) | 80 (81%) | 0.071 |
Note: Linear Regression Models were used to assess differences between groups with genetic status as the fixed factor and LEDD and age as covariates.
Abbreviations: BDI, Beck Depression Inventory; GDS, Geriatric Depression Scale; LEDD, Levodopa Equivalent Daily Dose; M/F, male/female; MDS‐UPDRS‐III, Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III; MDS‐UPDRS‐T, Movement Disorders Society Unified Parkinson's Disease Rating Scale Total; MOCA, Montreal Cognitive Assessment; NMSQ, Non‐Motor Symptoms Questionnaire; RBDQ, REM sleep Behavior Disorder Questionnaire; SCOPA‐AUT, Scale of Autonomic Function in PD; STAIS, State‐Trait Anxiety Inventory‐State; STAIT, State‐Trait Anxiety Inventory‐Trait.
Twenty‐four percent of GBA‐PD, 23% of LRRK2‐PD and 16% of iPD reported depressive episodes before diagnosis of PD, with no significant difference between groups (p=0.655) (Fig. 1). Contrarily, 16.5% of GBA‐PD received mood related medication before diagnosis compared with only 7.1% and 8.2% of LRRK2‐PD and iPD (p= 0.044) (Fig. 1). There was no difference in age of onset between those reporting depression and those without (p=0.126) nor was there a difference in age of onset between those receiving mood related medications and those who did not (p=0.436) in any of the groups. No between‐group differences in sex were detected between those reporting prodromal depression (iPD χ 2=0.588, LRRK2‐PD χ 2 =0.612 or GBA‐PD χ 2 =0.713).
Figure 1.
Depression and medication status of the study cohort. Linear Regression Models were used to assess differences between groups with genetic status as the fixed factor and LEDD and age as covariates. GBAPD, Glucocerebrosidase‐Parkinson's Disease; IPD, Idiopathic Parkinson's Disease; LRRK2‐PD, Leucine Rich Repeat Kinase 2‐Parkinson's Disease.
Depression prior to diagnosis of PD was correlated with depression at time of assessment in all three groups of participants (p<0.001), and with BDI scores at the time of assessment in iPD and GBA‐PD (p<0.001), but not in LRRK2‐PD.
At the time of baseline assessment, 130 patients (53% of iPD, 45% of LRRK2‐PD and 50% of GBA‐PD), were using some form of mood related medications (Table 2). SSRI's were used by 10% of iPD patients, 15% of LRRK2 patients, and 16% of GBA patients. Respectively, SNRI (6% vs. 4% vs. 4%), TCA (0% vs. 2% vs. 1%), and atypical antidepressant (2% vs. 0% vs. 6%) usage was similar among genotypes (p>0.153). There was no difference between the groups in the frequency of Amantadine or Dopamine agonists use (p>0.379). Lastly, groups were similar in the usage of Benzodiazepines and atypical antipsychotics (p>0.569) (Table 2).
TABLE 2.
Prevalence of medication type by genotype at time of assessment. Linear Regression Models were used to assess differences between groups with genetic status as the fixed factor
| Medication Categories | iPD (N=105) | LRRK2 (N=55) | GBA (N=98) | p value | |||
|---|---|---|---|---|---|---|---|
| Number of patients | % of genotype | Number of patients | % of genotype | Number of patients | % of genotype | ||
| No medications | 49 | 47% | 30 | 55% | 49 | 50% | 0.221 |
| Selective Serotonin Reuptake Inhibitors (SSRIs) | 11 | 10% | 8 | 15% | 16 | 16% | 0.637 |
| Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) | 6 | 6% | 2 | 4% | 4 | 4% | 0.744 |
| Tricyclic Antidepressants (TCAs) | 0 | 0% | 1 | 2% | 1 | 1% | 0.964 |
| Atypical Antidepressants (Mirtazapine, Vortioxetine, St. John's Wort) | 2 | 2% | 0 | 0% | 6 | 6% | 0.163 |
| Amantadine | 23 | 22% | 10 | 18% | 24 | 24% | 0.236 |
| Dopamine agonist | 21 | 20% | 10 | 18% | 20 | 20% | 0.094 |
| Benzodiazepine | 5 | 5% | 3 | 5% | 3 | 3% | 0.081 |
| Atypical antipsychotic | 1 | 1% | 1 | 2% | 2 | 2% | 0.648 |
Some PD signs and symptoms were more severe in patients receiving mood related medication as compared to those not taking medication at the time of assessment in GBA‐PD and LRRK2‐PD with only minor difference in the NMSQ in iPD (p=0.029) (Table 3). GBA‐PD and LRRK2‐PD who were using mood related medications also had higher LEDD scores compared with those that didn't (p<0.001). Self‐reported depression symptoms were similar between those taking mood related medications and those who did not in GBA‐PD and iPD (p>0.05). Among LRRK2‐PD, scores on BDI and STAI‐T were significantly higher in those treated with mood related medications compared to those that did not (p=0.040, p=0.026) (Fig. 2). BDI and GDS did not differ between genetic medicated and non‐medicated patients (p>0.366; Fig. 2). Interestingly, there was a trend for higher frequency of LRRK2‐PD with RBD within those treated with mood related medications than those without medications (p=0.071). However, there was no difference in the type of medications (ie, benzodiazepines) in the RBD subjects compared to those with no RBD in this subgroup (p>0.621). No difference between number of falls between participants taking mood related medications and those not, was detected (p>0.05) (Table 3).
TABLE 3.
Comparison of motor and non‐motor features based on mood‐related medication status
| Not receiving Meds | Receiving Meds | p value | ||
|---|---|---|---|---|
| IPD | N | 48 | 57 | |
| Age (y) | 67.27 ± 10.68 | 65.68 ± 10.32 | 0.441 | |
| Age diagnosed (y) | 65.22 ± 10.34 | 62.75 ± 10.31 | 0.224 | |
| Disease duration (y) | 2.56 ± 1.94 | 2.25 ± 1.81 | 0.857 | |
| LEDD (mg) | 159.78 ± 177.55 | 374.57 ± 310.68 | 0.314 | |
| MOCA | 23.53 ± 3.74 | 24.39 ± 3.62 | 0.234 | |
| RBDQ | 2.48 ± 2.16 | 3.43 ± 2.72 | 0.067 | |
| NMSQ | 6.29 ± 4.77 | 8.33 ± 4.37 | 0.029 | |
| SCOPA‐AUT | 15.68 ± 10.07 | 17.70 ± 10.19 | 0.329 | |
| MDS‐UPDRS‐III | 22.69 ± 13.79 | 23.00 ± 9.67 | 0.895 | |
| MDS‐UPDRS‐T | 35.59 ± 20.07 | 39.52 ± 15.96 | 0.408 | |
| BDI | 7.28 ± 5.93 | 8.34 ± 6.36 | 0.397 | |
| GDS | 3.21 ± 3.07 | 3.63 ± 2.60 | 0.455 | |
| STAI‐S | 52.07 ± 5.76 | 52.43 ± 5.41 | 0.746 | |
| STAI‐T | 54.93 ± 4.60 | 55.26 ± 6.11 | 0.766 | |
| Participants with RBD (% from total in the group) | 5 (29%) | 12 (70%) | 0.107 | |
| Mean number of falls | 4.1±2.1 | 5.3±1.1 | 0.383 | |
| LRRK2 | N | 30 | 25 | |
| Age (y) | 64.43 ± 10.64 | 66.12 ± 10.60 | 0.560 | |
| Age diagnosed (y) | 62.17 ± 10.26 | 61.96 ± 10.49 | 0.942 | |
| Disease duration (y) | 2.85 ± 2.34 | 3.01 ± 3.36 | 0.260 | |
| LEDD (mg) | 218.80 ± 277.70 | 555.88 ± 384.98 | <0.001 | |
| MOCA | 24.10 ± 4.52 | 24.36 ± 3.71 | 0.819 | |
| RBDQ | 2.33 ± 1.77 | 3.29 ± 2.56 | 0.124 | |
| NMSQ | 5.44 ± 3.42 | 7.78 ± 3.52 | 0.022 | |
| SCOPA‐AUT | 13.95 ± 8.41 | 19.91 ± 12.34 | 0.073 | |
| MDS‐UPDRS‐III | 17.50 ± 8.19 | 22.24 ± 8.91 | 0.045 | |
| MDS‐UPDRS‐T | 27.50 ± 12.13 | 39.00 ± 16.04 | 0.004 | |
| BDI | 5.92 ± 5.54 | 10.42 ± 9.20 | 0.040 | |
| GDS | 2.77 ± 3.55 | 4.77 ± 2.89 | 0.136 | |
| STAI‐S | 51.38 ± 5.74 | 54.13 ± 4.77 | 0.074 | |
| STAI‐T | 53.00 ± 4.27 | 55.96 ± 4.84 | 0.026 | |
| Participants with RBD (% from total in the group) | 1 (16.6%) | 5 (83.3%) | 0.071 | |
| Mean number of falls | 3.7±1.51 | 4.3±1.70 | 0.634 | |
| GBA | N | 47 | 47 | |
| Age (y) | 66.26 ± 10.09 | 64.35 ± 8.49 | 0.310 | |
| Age diagnosed (y) | 64.07 ± 9.33 | 60.31 ± 9.06 | 0.083 | |
| Disease duration (y) | 3.08 ± 2.46 | 3.25 ± 3.43 | 0.061 | |
| LEDD (mg) | 227.24 ± 246.35 | 499.90 ± 404.92 | <0.001 | |
| MOCA | 23.77 ± 4.20 | 23.17 ± 3.84 | 0.468 | |
| RBDQ | 3.34 ± 4.10 | 3.87 ± 2.47 | 0.458 | |
| NMSQ | 5.73 ± 4.45 | 9.48 ± 5.11 | 0.000 | |
| SCOPA‐AUT | 12.75 ± 9.87 | 18.59 ± 10.24 | 0.012 | |
| MDS‐UPDRS‐III | 20.50 ± 10.28 | 26.29 ± 12.81 | 0.016 | |
| MDS‐UPDRS‐T | 33.07 ± 16.33 | 45.85 ± 20.74 | 0.001 | |
| BDI | 8.16 ± 7.57 | 9.62 ± 7.67 | 0.364 | |
| GDS | 3.18 ± 2.84 | 3.80 ± 3.37 | 0.348 | |
| STAI‐S | 50.52 ± 4.77 | 52.09 ± 6.16 | 0.184 | |
| STAI‐T | 55.11 ± 4.37 | 54.64 ± 4.67 | 0.627 | |
| Participants with RBD (% from total in the group) | 10 (43%) | 13 (56.5%) | 0.459 | |
| Mean number of falls | 2.8±2.3 | 3.7±1.7 | 0.765 |
Note: Linear Regression Models were used to assess differences between groups with genetic status as the fixed factor.
Abbreviations: BDI, Beck Depression Inventory; GDS, Geriatric Depression Scale; IPD, Idiopathic Parkinson's Disease; LEDD, Levodopa equivalent daily dose; MDS‐UPDRS‐III, Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III; MDS‐UPDRS‐T, Movement Disorders Society Unified Parkinson's Disease Rating Scale Total; MOCA, Montreal Cognitive Assessment; NMSQ, Non‐Motor Symptoms Questionnaire; RBDQ, REM sleep Behavior Disorder Questionnaire; SCOPA‐AUT, Scale of Autonomic Function in PD; STAIS, State‐Trait Anxiety Inventory‐State; STAIT, State‐Trait Anxiety Inventory‐Trait.
Figure 2.
Medication effect on depressive symptoms (A) Geriatric Depression Scale (GDS) (B) Beck Depression Inventory (BDI) (C) State and Trait Anxiety Inventory (STAI). General Linear Models were used to assess differences between groups with genetic status as the fixed factor. GBA‐PD, Glucocerebrosidase‐Parkinson's Disease; IPD, Idiopathic Parkinson's Disease; LRRK2‐PD, Leucine Rich Repeat Kinase 2‐ Parkinson's Disease; STAI‐S, State‐Trait Anxiety Inventory‐State; STAIT, State‐Trait Anxiety Inventory‐Trait.
In a sub‐analysis including only traditional mood related medications (excluding dopamine agonists and amantadine) (Table 4), no differences were detected on any measure between iPD with and without medications. GBA‐PD taking mood related medications scored lower on STAI‐T (p=0.015) (less anxiety) compared with those not taking mood related medications. However, LRRK2‐PD who were receiving mood related medications had higher SCOPA‐AUT scores and higher total MDS‐UPDRS scores (p= 0.003 and p<0.001) and trended for higher BDI scores (p=0.069) and STAI‐S and T (p=0.054 and p=0.062) and RBDQ scores (p= 0.079) with a larger proportion of individuals classified as RBD (p=0.058) (Table 4).
TABLE 4.
Comparison of motor and non‐motor features based on anti‐depressive and anti‐anxiolitic medication consumption
| Not receiving Meds | Receiving Meds | p value | ||
|---|---|---|---|---|
| IPD | N | 89 | 16 | |
| Age diagnosed (y) | 63.85 ± 10.46 | 64.19 ± 10.15 | 0.906 | |
| Age (y) | 66.42 ± 10.60 | 66.44 ± 10.05 | 0.994 | |
| Disease duration (y) | 2.04 ± 2.03 | 2.93 ± 1.74 | 0.385 | |
| LEDD (mg) | 279.17 ± 282.92 | 247.44 ± 254.35 | 0.676 | |
| MOCA | 23.90 ± 3.98 | 24.50 ± 3.46 | 0.551 | |
| RBDQ | 2.96 ± 2.55 | 3.13 ± 3.42 | 0.816 | |
| NMSQ | 7.24 ± 4.63 | 8.25 ± 4.78 | 0.429 | |
| SCOPA‐AUT | 16.22 ± 9.95 | 19.75 ± 10.89 | 0.204 | |
| UPDRS‐III | 23.43 ± 11.91 | 19.69 ± 10.34 | 0.242 | |
| UPDRS‐T | 38.70 ± 17.76 | 35.13 ± 19.33 | 0.467 | |
| BDI | 7.63 ± 5.93 | 9.07 ± 7.41 | 0.408 | |
| GDS | 3.33 ± 2.96 | 4.00 ± 1.89 | 0.384 | |
| STAI‐S | 52.58 ± 5.68 | 50.53 ± 4.51 | 0.191 | |
| STAI‐T | 55.08 ± 5.54 | 55.27 ± 5.09 | 0.906 | |
| Participants with RBD (% from total in the group) | 7 (7%) | 10 (62.5%) | 0.541 | |
| Mean number of falls (in one year) | 6.12 ± 2.10 | 4.87 ± 3.21 | 0.383 | |
| LRRK2 | N | 46 | 9 | |
| Age (y) | 63.37 ± 10.53 | 74.56 ± 10.60 | 0.003 | |
| Age diagnosed (y) | 60.48 ± 10.30 | 70.22 ± 5.09 | 0.008 | |
| Disease duration (y) | 2.23 ± 2.09 | 2.76 ± 2.82 | 0.351 | |
| LEDD (mg) | 353.22 ± 365.85 | 468.11 ± 390.55 | 0.398 | |
| MOCA | 24.43 ± 4.52 | 23.11 ± 4.37 | 0.180 a | |
| RBDQ | 2.52 ± 2.01 | 4.00 ± 2.78 | 0.079 a | |
| NMSQ | 6.12 ± 3.54 | 8.63 ± 3.58 | 0.096 a | |
| SCOPA‐AUT | 15.19 ± 9.22 | 26.29 ± 14.70 | 0.003 a | |
| UPDRS‐III | 19.72 ± 9.28 | 19.33 ± 5.95 | 0.190 a | |
| UPDRS‐T | 32.67 ± 16.09 | 38.09 ± 8.69 | 0.004 a | |
| BDI | 7.63 ± 7.85 | 10.11 ± 5.55 | 0.069 a | |
| GDS | 3.41 ± 3.27 | 4.11 ± 3.64 | 0.192 a | |
| STAI‐S | 52.29 ± 5.36 | 54.56 ± 5.61 | 0.054 a | |
| STAI‐T | 54.15 ± 4.97 | 55.67 ± 3.46 | 0.062 a | |
| Participants with RBD (% from total in the group) | 2 (4.3%) | 4 (44.44%) | 0.058 a | |
| Mean number of falls | 4.22 ±2.01 | 3.91 ± 2.58 | 0.744 a | |
| GBA | N | 74 | 20 | |
| Age (y) | 64.85 ± 9.65 | 68.45 ± 6.97 | 0.123 | |
| Age diagnosed (y) | 61.78 ± 9.43 | 65.30 ± 9.15 | 0.141 | |
| Disease duration (y) | 2.28 ± 2.23 | 3.32 ± 2.84 | 0.053 | |
| LEDD (mg) | 359.61 ± 360.77 | 391.85 ± 374.56 | 0.726 | |
| MOCA | 23.46 ± 4.15 | 22.80 ± 3.45 | 0.519 | |
| RBDQ | 3.62 ± 3.64 | 3.94 ± 2.23 | 0.477 | |
| NMSQ | 7.55 ± 5.38 | 8.39 ± 4.53 | 0.550 | |
| SCOPA‐AUT | 16.00 ± 11.40 | 15.17 ± 7.97 | 0.774 | |
| UPDRS‐III | 23.30 ± 12.84 | 22.65 ± 7.91 | 0.831 | |
| UPDRS‐T | 38.91 ± 20.92 | 39.30 ± 12.58 | 0.936 | |
| BDI | 8.90 ± 7.73 | 8.63 ± 8.15 | 0.896 | |
| GDS | 3.57 ± 3.11 | 3.58 ± 3.38 | 0.989 | |
| STAI‐S | 51.13 ± 5.26 | 52.22 ± 5.75 | 0.448 | |
| STAI‐T | 55.40 ± 4.35 | 52.50 ± 4.57 | 0.015 | |
| Participants with RBD (% from total in the group) | 12 (16%) | 11 (65%) | 0.101 | |
| Mean number of falls | 2.11 ± 1.97 | 3.29 ± 2.21 | 0.433 |
Note: Linear Regression Models Linear Regression Models were used to assess differences between groups with genetic status as the fixed factor.
Abbreviations: BDI, Beck Depression Inventory; GDS, Geriatric Depression Scale; IPD, Idiopathic Parkinson's Disease; LEDD, Levodopa equivalent daily dose; MDS‐UPDRS‐III, Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III; MDS‐UPDRS‐T, Movement Disorders Society Unified Parkinson's Disease Rating Scale Total; MOCA, Montreal Cognitive Assessment; NMSQ, Non‐Motor Symptoms Questionnaire; RBDQ, REM sleep Behavior Disorder Questionnaire; SCOPA‐AUT, Scale of Autonomic Function in PD; STAIS, State‐Trait Anxiety Inventory‐State; STAIT, State‐Trait Anxiety Inventory‐Trait.
Adjusted for age and age at diagnosis.
Discussion
This multi‐faceted cross‐sectional study examined the relationship between genotype (LRRK2 and GBA) and the non‐motor phenotypes of mood disorders among early‐stage PD. No between group differences on standardized questionnaires assessing depression and anxiety were detected among our study groups. Prior to diagnosis of PD, approximately 20% of patients had affective symptoms, regardless of genotype. Out of these, however, a significantly greater portion of GBA‐PD received mood related medications than LRRK2‐PD and iPD. Patients reporting mood symptoms did not show an earlier age of onset of PD diagnosis. LRRK2‐PD and GBA‐PD who were receiving mood related medications, showed more severe motor and non‐motor symptoms compared to those that did not. Lastly, LRRK2‐PD who were taking mood related medications were still experiencing more severe depression and anxiety symptoms attesting inefficient treatments in this population.
There are mixed findings in the literature regarding differences in phenotype between LRRK2 and GBA carriers. A study by Liu et al showed equal prevalence of pre‐diagnostic symptoms among GBA and LRRK2 patients, 29 while other studies show that the LRRK2 genotype has a milder phenotype compared to iPD including mood disorders. 15 Further, among early onset LRRK2‐PD patients, no significant differences in mood disorder measures were observed compared to iPD. 30 Our findings are in partial agreement with these studies, as the percentage of LRRK2‐PD with mood related complaints was similar to that of iPD prior to disease diagnosis. In addition, comparison of the GDS and BDI scores between non‐medicated patients, revealed no significant differences between the genetic groups (Fig. 2). Interestingly, comparison between medicated and non‐medicated patients in the GBA and iPD groups revealed no differences in BDI and GDS scores however, LRRK2‐PD treated with mood related medications, experienced higher depression and anxiety compared to non‐treated patients. Restricting the analysis to use of only mood related medications (excluding dopamine agonists and amantadine) did not detect between group differences among iPD but among LRRK2‐PD still resulted in a trend for worse affective symptoms, while among GBA‐PD resulted in less anxiety among treated patients. A possible explanation to the less efficacious effect of the mood related medication in LRRK2‐PD, could be related to the decreased serotonergic binding that was previously reported in LRRK2. 21 Together, these findings may suggest that serotonin mediating antidepressants such as SSRIs might not be effective for LRRK2 patients as for GBA‐PD, or that they might require higher doses of such medications. However, our study was underpowered to specifically address this question.
Previous studies have reported that GBA‐PD are more likely to have mood disorders compared with iPD patients. 14 , 31 In the current study, the percent of GBA‐PD who had prodromal depression was similar to that of the two other groups however, the percentage of GBA‐PD who received medication to alleviate mood disorders prior to diagnosis was significantly higher than that of LRRK2‐PD and iPD. The difference between the reported symptoms and the use of medication likely stems from the subjective perception specifically as it relates to recall. This recall also made the exploration of severity of symptoms extremely difficult and biased. We can only speculate that depressive symptoms were more severe in GBA‐PD compared to the other groups of participants prior to the diagnosis of PD. Interestingly, GBA‐PD treated with mood related medications showed effective treatment, as their symptoms were similar or better compared with non‐medicated patients. A recent study has shown that mutations in the GBA gene can cause a decrease in serotonin secretion, in addition to dopamine. 32 This could serve as an explanation why GBA was more responsive to serotonin altering medications.
Currently, SSRI's and TCA's are the most commonly prescribed medications for depression in PD. 10 Such antidepressants have been implicated with increased fall risk among older individuals 33 as well as in patients with PD. 34 This is specifically important considering the high risk of falls in PD. Our study did not find an association between falls, depression, or mood related medications. It is possible that the early stage of disease among our cohort masks this effect.
Another drawback to antidepressant use in these patients is the increased frequency of RBD. 35 Accumulating evidence suggest that LRRK2‐PD experience less RBD than other genetic or idiopathic groups. 36 Our results contribute to this knowledge with a trend for lower frequency of RBD in LRRK2‐PD compared with the two other groups of participants. Interestingly however, when examining within groups, there was a higher frequency of RBD in LRRK2‐PD patients who were taking mood related medication as compared to those who did not (5 vs. 1). This was also apparent when we only explored use of SSRI's and SNRI's. One explanation is the interrelation between non‐motor symptoms. Alternatively, the information on RBD was collected via the RBDQ with a cut‐off of 6 reflecting RBD and was not confirmed by polysomnography. It is possible that subjective report may be related to depression and self‐perception. Further longitudinal studies are needed to evaluate the effect of mood related disorders on disease progression in genetic PD.
The MoCA scores of our cohort, which has relatively short disease duration, might seem initially low. It has been shown in several publications that even in early‐stage PD, cognitive function may be impaired in patients with PD. 37 , 38 This is specifically apparent in GBA‐PD. In addition, we used the validated Hebrew version of the MoCA which despite content validity, seems to be more difficult than the English version. 39
These results are presented with some limitations. First, the report on depression, anxiety and mood related medication use prior to PD diagnosis relied heavily on patient recall and was assessed by a neurologist and not by a psychiatrist and without lifetime psychiatric assessment instruments. The use of mood related medications as a measure of depression might under‐represent the prevalence or onset of depression, as many patients will not be treated with medications, or with non‐pharmacological measures. Further, the data did not take into account if the medications were first line treatment or subsequent to previously failed mood related prescriptions. There was no method of assessing whether the knowledge of genetic status affected mood among the participants.
Nonetheless, the study, with this relatively large cohort of genetic PD patients, provides new insight into the complex relationship between mood‐related symptoms and treatment among genotypic variants. GBA‐PD were shown to have higher rates of treatment for mood disorders prior to the diagnosis of PD but with an increased response to treatment compared to iPD and LRRK2‐PD after diagnosis. While LRRK2‐PD, receiving treatment for mood related symptoms, still scored higher on mood related questionnaires suggesting the need for better precision medicine in these genetic groups.
Author Roles
1) Research project: A. Conception, B. Organization, C. Execution; 2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3) Manuscript: A. Writing of the first draft, B. Review and Critique.
J.D.: 1B, 3A
N.O.: 1C, 3B
B.C.: 1C, 3B
N.G.: 1A, 3B
M.K.: 1C, 3B
J.C.S.: 1A, 3B
J.M.C.: 3B
M.G.W.: 1C, 3B
O.G.: 3B
A.O.U.: 1A, 3B
A.M.: 1A, 1B, 1C, 2A, 3B
A.T.: 1A, 1B, 1C, 2A, 3B
Disclosures
Ethical Compliance Statement: The Tel‐Aviv Medical Center ethics committee approved this study Each participant signed a written consent form All authors have read and complied with the journals’ ethical guidelines
Funding Sources and Conflicts of Interest: This study was funded by Biogen. None of the authors report relevant conflict of interest.
Financial Disclosures for Previous 12 Months: JD – Nothing to disclose NO – Nothing to disclose BSC – Nothing to disclose NG – Serves on the Editorial Board of the Journal of Parkinson's Disease. Serves as consultant to Biogen, Genzyme‐Sanofi, Sionara, NeuroDerm, Intec Pharma, Pharma2B, Denali Neuron23 and Abbvie. Receives royalties from Lysosomal Therapeutics (LTI) and payment for lectures from Abbvie, Sanofi‐Genzyme, Bial and Movement Disorder Society. Received research support from the Michael J. Fox Foundation, the National Parkinson Foundation, the European Union 7th Framework Program, the Israel Science Foundation, Teva NNE program, Biogen, LTI, and Ionis. M.K. – Payment for lectures from Abbvie and Teva. J.C.S. – Employee and shareholder in Biogen, Inc. J.M.C. – A former employee and shareholder in Biogen, Inc. M.G.W. – Nothing to disclose. O.G. – Nothing to disclose. A.O.U. – Research support from the Michael J. Fox Foundation, Chaya Charitable Fund and Biogen and payment for lectures from Sanofi Genzyme and Pfizer. A.M. – Serving as advisor to Neuroderm. A.T. – Receiving honoraria from Abbvie Israel.
Acknowledgements
We would like to thank the patients for their participation in this study.
Anat Mirelman and Avner Thaler contributed equally to this publication.
References
- 1. Tan LC. Mood disorders in Parkinson's disease. Parkinsonism Relat Disord 2012;18(Suppl 1):S74–S76. [DOI] [PubMed] [Google Scholar]
- 2. Schapira AHV, Chaudhuri KR, Jenner P. Non‐motor features of Parkinson disease. Nat Rev Neurosci 2017;18(8):509. [DOI] [PubMed] [Google Scholar]
- 3. Postuma RB et al. Identifying prodromal Parkinson's disease: pre‐motor disorders in Parkinson's disease. Mov Disord 2012;27(5):617–626. [DOI] [PubMed] [Google Scholar]
- 4. Seppi K et al. Update on treatments for nonmotor symptoms of Parkinson's disease‐an evidence‐based medicine review. Mov Disord 2019;34(2):180–198. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Ryan M, Eatmon CV, Slevin JT. Drug treatment strategies for depression in Parkinson disease. Expert Opin Pharmacother 2019;20(11):1351–1363. [DOI] [PubMed] [Google Scholar]
- 6. Schwab RS, England AC Jr, Poskanzer DC, Young RR, et al. Amantadine in the treatment of Parkinson's disease. JAMA 1969;208(7):1168–1170. [PubMed] [Google Scholar]
- 7. Barone P et al. Pramipexole for the treatment of depressive symptoms in patients with Parkinson's disease: a randomised, double‐blind, placebo‐controlled trial. Lancet Neurol 2010;9(6):573–580. [DOI] [PubMed] [Google Scholar]
- 8. Stryjer R et al. Amantadine as augmentation therapy in the management of treatment‐resistant depression. Int Clin Psychopharmacol 2003;18(2):93–96. [DOI] [PubMed] [Google Scholar]
- 9. Bomasang‐Layno E et al. Antidepressive treatments for Parkinson's disease: A systematic review and meta‐analysis. Parkinsonism Relat Disord 2015;21(8):833–842. discussion 833. [DOI] [PubMed] [Google Scholar]
- 10. Connolly B, Fox SH. Treatment of cognitive, psychiatric, and affective disorders associated with Parkinson's disease. Neurotherapeutics 2014;11(1):78–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Gan‐Or Z et al. LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson disease. Neurogenetics 2010;11(1):121–125. [DOI] [PubMed] [Google Scholar]
- 12. Clark LN et al. Mutations in the glucocerebrosidase gene are associated with early‐onset Parkinson disease. Neurology 2007;69(12):1270–1277. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Ysselstein D et al. LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson's disease patients. Nat Commun 2019;10(1):5570. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Swan M et al. Neuropsychiatric characteristics of GBA‐associated Parkinson disease. J Neurol Sci 2016;370:63–69. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Kozlovski T et al. Hierarchical Data‐Driven Analysis of Clinical Symptoms Among Patients With Parkinson's Disease. Front Neurol 2019;10:531. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Saunders‐Pullman, R. , et al., Progression in the LRRK2‐Asssociated Parkinson Disease Population. JAMA Neurol, 2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Goldwurm S et al. LRRK2 G2019S mutation and Parkinson's disease: a clinical, neuropsychological and neuropsychiatric study in a large Italian sample. Parkinsonism Relat Disord 2006;12(7):410–419. [DOI] [PubMed] [Google Scholar]
- 18. Belarbi S et al. LRRK2 G2019S mutation in Parkinson's disease: a neuropsychological and neuropsychiatric study in a large Algerian cohort. Parkinsonism Relat Disord 2010;16(10):676–679. [DOI] [PubMed] [Google Scholar]
- 19. Moreira‐Junior RE et al. Possible association between the lrrk2 gene and anxiety behavior: a systematic literature review. J Neurogenet 2022;36(4):98–107. [DOI] [PubMed] [Google Scholar]
- 20. Omer N et al. A Possible Modifying Effect of the G2019S Mutation in the LRRK2 Gene on GBA Parkinson's Disease. Mov Disord 2020;35(7):1249–1253. [DOI] [PubMed] [Google Scholar]
- 21. Wile DJ et al. Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross‐sectional studies. Lancet Neurol 2017;16(5):351–359. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Postuma RB et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord 2015;30(12):1591–1601. [DOI] [PubMed] [Google Scholar]
- 23. Goldstein O et al. Revisiting the non‐Gaucher‐GBA‐E326K carrier state: Is it sufficient to increase Parkinson's disease risk? Mol Genet Metab 2019;128(4):470–475. [DOI] [PubMed] [Google Scholar]
- 24. Beutler E et al. Gaucher disease: gene frequencies in the Ashkenazi Jewish population. Am J Hum Genet 1993;52(1):85–88. [PMC free article] [PubMed] [Google Scholar]
- 25. Ngo AB, Smith KM. Patient and Clinician Impressions of Cognitive Impairment in Parkinson's Disease. J Parkinsons Dis 2020;10(4):1695–1698. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Levin BE, Llabre MM, Weiner WJ. Parkinson's disease and depression: psychometric properties of the Beck Depression Inventory. J Neurol Neurosurg Psychiatry 1988;51(11):1401–1404. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Kvaal K et al. The Spielberger State‐Trait Anxiety Inventory (STAI): the state scale in detecting mental disorders in geriatric patients. Int J Geriatr Psychiatry 2005;20(7):629–634. [DOI] [PubMed] [Google Scholar]
- 28. Tomlinson CL et al. Systematic review of levodopa dose equivalency reporting in Parkinson's disease. Mov Disord 2010;25(15):2649–2653. [DOI] [PubMed] [Google Scholar]
- 29. Liu SY et al. Prevalence of pre‐diagnostic symptoms did not differ between LRRK2‐related, GBA‐related and idiopathic patients with Parkinson's disease. Parkinsonism Relat Disord 2018;57:72–76. [DOI] [PubMed] [Google Scholar]
- 30. Chen Y et al. Evaluating the Role of SNCA, LRRK2, and GBA in Chinese Patients With Early‐Onset Parkinson's Disease. Mov Disord 2020;35(11):2046–2055. [DOI] [PubMed] [Google Scholar]
- 31. Jesus S, Huertas I, Bernal‐Bernal I, et al. GBA Variants Influence Motor and Non‐Motor Features of Parkinson's Disease. PLoS One 2016;11(12):e0167749. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. de la Fuente C et al. Inhibition of neuronal mitochondrial complex I or lysosomal glucocerebrosidase is associated with increased dopamine and serotonin turnover. Neurochem Int 2017;109:94–100. [DOI] [PubMed] [Google Scholar]
- 33. Marcum ZA et al. Antidepressant Use and Recurrent Falls in Community‐Dwelling Older Adults: Findings From the Health ABC Study. Ann Pharmacother 2016;50(7):525–533. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Schrag A et al. Why do patients with Parkinson's disease fall? A cross‐sectional analysis of possible causes of falls. NPJ Parkinsons Dis 2015;1:15011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Postuma RB et al. Antidepressants and REM sleep behavior disorder: isolated side effect or neurodegenerative signal? Sleep 2013;36(11):1579–1585. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Pont‐Sunyer C et al. Sleep Disorders in Parkinsonian and Nonparkinsonian LRRK2 Mutation Carriers. PLoS One 2015;10(7):e0132368. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Alcalay RN et al. Cognitive performance of GBA mutation carriers with early‐onset PD: the CORE‐PD study. Neurology 2012;78(18):1434–1440. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Schejter‐Margalit T et al. Quantitative digital clock drawing test as a sensitive tool to detect subtle cognitive impairments in early stage Parkinson's disease. Parkinsonism Relat Disord 2021;90:84–89. [DOI] [PubMed] [Google Scholar]
- 39. Xu Y et al. Differences in performance on English and Hebrew versions of the MoCA in Parkinson's patients. Clin Park Relat Disord 2020;3:100042. [DOI] [PMC free article] [PubMed] [Google Scholar]