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. 2016 Apr 19;37(8):2894–2903. doi: 10.1002/hbm.23213

Free‐water and BOLD imaging changes in Parkinson's disease patients chronically treated with a MAO‐B inhibitor

Roxana G Burciu 1, Edward Ofori 1, Priyank Shukla 1, Ofer Pasternak 2,3, Jae Woo Chung 1, Nikolaus R McFarland 4,5, Michael S Okun 4,5,6, David E Vaillancourt 1,4,7,✉
PMCID: PMC4945383  NIHMSID: NIHMS775199  PMID: 27089850

Abstract

Rasagiline is a monoamine oxidase type B inhibitor that possesses no amphetamine‐like properties, and provides symptomatic relief in early and late stages of Parkinson's disease (PD). Data in animal models of PD suggest that chronic administration of rasagiline is associated with structural changes in the substantia nigra, and raise the question whether the structure and function of the basal ganglia could be different in PD patients treated chronically with rasagiline as compared with PD patients not treated with rasagiline. Here, we performed a retrospective cross‐sectional magnetic resonance imaging (MRI) study at 3 T that investigated nigrostriatal function and structure in PD patients who had taken rasagiline before testing (∼8 months), PD who had not taken rasagiline before testing, and age‐matched controls. The two PD groups were selected a priori to not differ significantly in age, sex, disease duration, severity of symptoms, cognitive status, and total levodopa equivalent daily dose of medication. We evaluated percent signal change in the posterior putamen during force production using functional MRI, free‐water in the posterior substantia nigra using diffusion MRI, and performance on a bimanual coordination task using a pegboard test. All patients were tested after overnight withdrawal from antiparkinsonian medication. The rasagiline group had greater percent signal change in the posterior putamen, less free‐water in the posterior substantia nigra, and better performance on the coordination task than the group not taking rasagiline. These findings point to a possible chronic effect of rasagiline on the structure and function of the basal ganglia in PD. Hum Brain Mapp 37:2894–2903, 2016. © 2016 Wiley Periodicals, Inc.

Keywords: Parkinson's disease, rasagiline, task‐based fMRI, free‐water diffusion MRI, nigrostriatal regions

INTRODUCTION

Parkinson's disease (PD) is a movement disorder characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta, and subsequent dopamine deficiency of the striatum [Dickson, 2012; Kordower et al., 2013]. Treatment options in PD typically include levodopa, dopamine agonists, and monoamine oxidase type B (MAO‐B) inhibitors [Jankovic and Aguilar, 2008]. The latter, MAO‐B inhibitors, enhance dopaminergic activity by prolonging both endogenously and exogenously derived dopamine [Fernandez and Chen, 2007].

In recent years, rasagiline, a selective and irreversible inhibitor of monoamine oxidase, has received increased attention because unlike other MAO‐B inhibitors it is not metabolized into amphetamine‐like derivatives, and is well‐tolerated in patients with PD [Chen et al., 2007]. Studies have shown that a daily dose of 1 mg is effective in reducing the severity of motor symptoms in patients with early stage PD, as well as the “off” time in more advanced PD patients who exhibit motor fluctuations and levodopa‐induced dyskinesia [Chen et al., 2007; Obeso et al., 2010; Olanow et al., 2009; Rascol et al., 2005]. The neural mechanisms underlying the symptomatic effects of rasagiline have been investigated in rodents with nigrostriatal degeneration caused by striatal injection of 6‐hydroxydopamine (6‐OHDA) or lactacystin. Chronic treatment with rasagiline in these animal models of PD was associated with reduced dopaminergic cell loss in the substantia nigra [Blandini et al., 2004; Zhu et al., 2008 ]. Collectively, animal data raise the question whether there could be potential long‐lasting functional and structural brain changes associated with chronic administration of rasagiline.

In this study we aimed to test the hypothesis that functional and structural brain changes as a result of chronic treatment with rasagiline in PD patients can be detected by noninvasive neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and diffusion MRI. Over the years, our group has developed a robust fMRI grip force protocol that is sensitive to changes in the functional state of the basal ganglia. Briefly, the task requires participants to produce rapid cycles of contraction‐relaxation by pushing on a force sensor while lying in the MRI scanner. This task was selected because precise and rapid adjustment of muscle contraction and relaxation are crucial to motor behavior, and are extensively evaluated in part III of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS‐III), the gold standard for the assessment of motor symptoms in PD. In PD, the putamen is underactive during force production, and this finding is consistent across multiple studies and stages of the disease [Burciu et al., 2015; Neely et al., 2015; Planetta et al., 2014; Prodoehl et al., 2010; Spraker et al., 2010].

Estimation of the effects of antiparkinsonian medication on the degenerative process in the substantia nigra in PD is highly dependent on the sensitivity and specificity of outcome measures. Therefore, in addition to task‐based fMRI, in this retrospective cross‐sectional study we also used a novel free‐water diffusion MRI technique to examine the nigrostriatal regions in two PD cohorts with and without rasagiline treatment history. Recently, a novel approach of analyzing diffusion MRI data has been proposed, and consists of a bi‐tensor model that separates the diffusion properties of water in brain tissue from those of water in extracellular space [Pasternak et al., 2009]. This procedure allows the calculation of the fractional volume of free‐water within a voxel (i.e., water molecules that are not restricted by the cellular environment and do not display a directional dependence) which is expected to increase with atrophy‐based neurodegeneration [Wang et al., 2011]. Using this technique we showed that free‐water in the posterior substantia nigra was elevated in PD compared with control subjects in a single‐site cohort and a multi‐site cohort from the Parkinson's Progressive Marker Initiative [Ofori et al., 2015a]. In addition, free‐water is elevated in the substantia nigra of other forms of parkinsonism such as multiple system atrophy and progressive supranuclear palsy [Ofori et al., 2015a; Planetta et al., 2016]. Most importantly, in a prospective longitudinal design, free‐water in the posterior substantia nigra was found to increase with longitudinal progression of PD over 1 year, and predicted subsequent changes in bradykinesia [Ofori et al., 2015b].

For this study we identified a cohort of PD patients chronically treated with rasagiline either as monotherapy or adjunct to standard dopaminergic therapy, and another cohort of PD patients never exposed to rasagiline or other MAO‐B inhibitor. Notably, the two PD groups were selected a priori to not differ significantly in age, sex, disease duration, severity of symptoms, cognitive status, and total levodopa equivalent daily dose of medication. Because of a potential cumulative effect of successive doses of rasagiline on MAO‐B enzyme inhibition, we hypothesized that PD patients who had taken rasagiline as part of their antiparkinsonian treatment regimen would have greater force‐related fMRI activity in the posterior putamen, and less structural changes (i.e., reduced free‐water) in the posterior substantia nigra than PD patients who had not taken rasagiline or other MAO‐B inhibitor. We also evaluated the possibility that chronic administration of rasagiline may affect motor behavior. For this, we selected a bimanual coordination task from the Purdue Pegboard Test since bimanual coordination is known to be impaired in patients with PD [Serrien et al., 2000]. We hypothesized that PD patients who had been treated with rasagiline would perform better on the pegboard test that involves bimanual coordination than those who had not been treated with rasagiline.

MATERIALS AND METHODS

Participants

A total of 52 individuals participated in the current retrospective cross‐sectional imaging study between 2012 and 2014: 34 patients with early stage PD, and 18 healthy age‐matched controls (Table 1). The experiment was approved by the Institutional Review Board, and all participants provided informed consent before participating in the study. PD patients were referred from the University of Florida Center for Movement Disorders and Neurorestoration where they were diagnosed by a movement disorder specialist using established criteria [Hughes et al., 2001]. Control participants were recruited via advertisements from the local and surrounding communities in North Central Florida, and had no history of neuropsychiatric or neurological problems. The PD patients were grouped into patients who had taken rasagiline before testing [n = 16, 12 males, 4 females, mean treatment duration in months (±SD) = 8.0 (8.6)], and patients who had not taken rasagiline or any other MAO‐B inhibitor for up to 90 days before testing (n = 18, 15 males, 3 females). The rasagiline group included thirteen patients who had been medicated with 1 mg/day of rasagiline, and three patients who had been medicated with 0.5 mg/day. Two PD patients had taken rasagiline as monotherapy, whereas the remaining fourteen PD patients had taken rasagiline along with carbidopa‐levodopa and/or dopamine agonists (Supporting Information Table I). Importantly, PD patients were tested approximately 12 to 14 h after overnight withdrawal of antiparkinsonian medication [Langston et al., 1992]. The half‐life of antiparkinsonian medication can be found in the footnote of Supporting Information Table I. The levodopa equivalent daily dose (LEDD) of each drug and a total LEDD were calculated according to previously published recommendations [Tomlinson et al., 2010]. Overall, the two PD groups did not differ in age, male to female ratios, disease duration (i.e., time since diagnosis), severity of motor symptoms, cognitive status, and total LEDD. Motor symptoms and cognitive status were assessed using part III of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS‐III) and the Montreal Cognitive Assessment (MoCA), respectively [Goetz et al., 2008; Nasreddine et al., 2005]. The MDS‐UPDRS‐III was used to calculate the following scores: total motor severity, bradykinesia (items 4–8, 14), and lateralized subscores consisting of the sum of side‐specific items for limbs only (items 3–8, 15–17) (Table 1). In the table, lateralized scores are listed as MDS‐UPDRS‐III for the tested side, and MDS‐UPDRS‐III for the other side.

Table 1.

Demographics, clinical and force data

Variables PD + rasagiline PD – rasagiline Controls p‐value
Sample Size 16 18 18 –
Age 64.3 ( ± 10.5) 63.8 ( ± 7.1) 63.5 ( ± 9.4) 0.937
Gender (M/F) 12/4 15/3 8/10 0.033
Handedness (L/R) 3/13 2/16 3/15 0.983
Hand Tested (L/R) 6/10 9/9 7/11 0.816
Hand Tested (Dom/Non‐Dom) 9/7 9/9 12/6 0.791
Hand Tested (MVC) 69.0 ( ± 23.3) 74.7 ( ± 19.7) 68.9 ( ± 21.9) 0.441
Hoehn and Yahr (I/II) 6/10 2/16 – 0.304
Disease Duration (Years) 2.3 ( ± 2.5) 3.5 ( ± 1.9) – 0.304
More affected side (L/R) 6/10 9/9 – 0.742
Total LEDD 566.0 (329.5) 646.2 (412.3) – 0.533
MDS‐UPDRS‐III – Total 24.0 ( ± 12.0) 29.3 ( ± 8.8) 2.9 ( ± 2.3) 0.306
MDS‐UPDRS‐III – Bradykinesia 10.6 ( ± 6.7) 12.1 ( ± 4.7) 0.7 ( ± 0.9) 0.456
MDS‐UPDRS‐III – Tested Side 12.3 ( ± 4.8) 12.6 ( ± 4.6) 1.5 ( ± 1.1) 0.885
MDS‐UPDRS‐III – Other Side 6.5 ( ± 4.7) 9.0 ( ± 4.5) 1.2 ( ± 1.1) 0.127
PPB Bimanual Coordination 16.4 ( ± 4.6) 13.1 ( ± 4.0) 20.2 ( ± 3.4) 0.006
MoCA 25.8 ( ± 2.6) 25.5 ( ± 2.6) 27.0 ( ± 1.9) 0.366
Mean Force 11.3 (4.5) 11.4 (4.6) 12.9 (4.3) 0.544
SD of Force 0.3 (0.2) 0.4 (0.2) 0.3 (0.1) 0.544
Rate Up 15.6 (9.4) 17.1 (9.6) 21.8 (10.6) 0.372
Rate Down −23.4 (16.2) −22.7 (15.5) −32.4 (14.2) 0.520
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Data are count or mean (± SD). P values correspond to between‐group statistics, and are FDR corrected.

Dom = dominant, F = female, L = left, LEDD = levodopa equivalent daily dose, M = male, MDS‐UPDRS‐III = Part III of the Movement Disorder Society Unified Parkinson's Disease Rating Scale, MoCA = Montreal Cognitive Assessment, MVC = maximum voluntary contraction, Non‐Dom = non‐dominant, PD = Parkinson's disease, PPB = Purdue Pegboard Test, R = right.

Bimanual coordination was tested using the Purdue Pegboard Test and consisted in the total number of pins placed on the pegboard within 1 minute, with both hands working simultaneously [Desrosiers et al., 1995].

fMRI Force Generation Task

Before entering the MRI scanner, all participants were trained on the task. At the beginning of the training session, each participant's maximum voluntary contraction (MVC) was measured using a Jamar hydraulic pinch gauge. Participants had to produce a contraction of maximum force for approximately 5 s using a pinch grip (thumb, index, and middle finger) on three consecutive trials. The three trials were separated by 30 s rest periods. The corresponding output values were used to compute an average MVC that served to normalize force data across participants. For each participant, the target force level was set at 15% of the MVC. PD were required to produce force with the more affected hand, while for controls we balanced hand use (right vs. left) (Table 1). The more affected hand in PD was defined using the upper limb items from the MDS‐UPDRS‐III scale.

The fMRI protocol consisted of a block‐design that alternated force and rest blocks as follows: 30 s rest, 30 s force with performance feedback, 12.5 s rest, and 30 s force without performance feedback [Burciu et al., 2015; Neely et al., 2015; Planetta et al., 2014; Prodoehl et al., 2010; Spraker et al., 2010]. This sequence was repeated four times and there was an additional 30‐s rest period following the final block of force without performance feedback. Thus, the scan lasted 7 min and 33 s. Throughout the scan, two bars were displayed on an LCD monitor that participants could see through a mirror mounted on the MRI head coil: a target bar, and a force bar. A change in color of the force bar cued participants to either push or release the force sensor. Green was a go‐signal for producing and sustaining force (2 s), while red indicated a rest period (1 s). Force was produced in the presence of performance feedback as well as in the absence of performance feedback (four blocks per condition). In the feedback condition, the target bar was stationary at 15% MVC, while the force bar moved in the vertical plane according to the force output. Instructions were to produce force, in order to bring the force bar on top of the target bar for each 2 s period. In the no‐feedback condition, both target and force bars were stationary. Participants were required to produce and maintain a 15% MVC force during each 2 s period without feedback, and the timing of the force contractions was controlled by the same green and red bars.

MRI Data Acquisition Protocol

MRI was performed on a 3 T system (Philips Achieva) equipped with a 32‐channel SENSE head coil. Functional images were obtained using a T2*‐weighted, single shot, echo‐planar pulse sequence with the following parameters: repetition time = 2,500 ms, echo time = 30 ms, flip angle = 80°, field of view = 240 mm2, acquisition matrix = 80 × 80, voxel size = 3 mm isotropic with no gap between slices (n = 46). Whole brain diffusion imaging data was acquired using a single‐shot spin echo EPI sequence: repetition time = 7,748 ms, echo time = 86 ms, flip angle = 90°, field of view = 224 × 224 mm, voxel size = 2 mm isotropic with no gap between slices (n = 60), diffusion gradient (monopolar) directions = 64, diffusion gradient timing DELTA/delta = 42.4/10 ms, b values: 0, 1,000 s/mm2, fat suppression using SPIR, in‐plane, SENSE factor = 2. Finally, a three‐dimensional (3D) T1‐weighted image was collected: repetition time = 8.2 ms, echo time = 3.7 ms, flip angle = 8°, field of view = 240 mm2, acquisition matrix = 240 × 240, voxel size = 1 mm isotropic with no gap between slices (n = 170). All scans were acquired axially.

fMRI Data Analysis

Consistent with previous studies, the fMRI and T1‐weighted scans of those participants who performed the task with their left hand were flipped along the midline before preprocessing [Burciu et al., 2015; Neely et al., 2015; Planetta et al., 2014; Prodoehl et al., 2013, 2010; Spraker et al., 2010]. Data analysis was performed using Analysis of Functional NeuroImages (AFNI) and included the following steps: (1) removal of the first four volumes of the functional scan to allow for T1 equilibration effects, (2) slice timing and head motion correction, (3) normalization of the signal in each voxel at each time point by the mean of its time series, (4) registration of each volume of the functional data set to its first volume, (5) co‐registration of the functional scan with the structural scan, (6) spatial normalization of the structural scan to the MNI152 template, (7) reslicing of the functional scan in MNI space using the normalization parameters from the previous step, (8) smoothing of the functional scan with a Gaussian kernel of 4 mm full width at half‐maximum (FWHM). Finally, fMRI data were regressed to a simulated hemodynamic response function for the task sequence (using the 3Ddeconvolve function in AFNI), and percent signal change in the posterior putamen contralateral to the hand tested was calculated across the four force blocks for each TR. Next, a mean percent signal change was calculated for a 12.5 s period (5 TRs out of 12) towards the end of the force block. This time interval was selected based on previous results showing a significant group (controls vs. PD) by TR interaction with task progression in nuclei of the basal ganglia [Spraker et al., 2010]. The posterior putamen region of interest (ROI) was defined based on the Basal Ganglia Human Area Template (BGHAT) [Prodoehl et al., 2008]. In addition, in order to better estimate rasagiline‐related fMRI effects we also included a control ROI in a region of the brain associated with complex non‐motor functions (i.e., angular gyrus) [Seghier, 2013]. For this, the Automated Anatomical Labeling Template (AAL) was used to extract the angular gyrus contralateral to the hand tested [Tzourio‐Mazoyer et al., 2002].

Diffusion MRI Data Analysis

FMRIB Software Library (FSL, http://www.fmrib.ox.ac.uk/fsl/) and custom UNIX shell scripts were used to preprocess the data. Diffusion MRI data were not flipped. Each diffusion scan was eddy current and head motion corrected. Diffusion gradients were compensated for rotations, and nonbrain tissue was removed. Free‐water maps were calculated from the corrected volumes using a custom code written in MATLAB R2013a (The Mathworks, Natick, MA) [Ofori et al., 2015a, 2015b]. Briefly, a bitensor model was applied, where signal attenuation is computed from two compartments: one that models tissue and another that models free‐water. Next, the b0 images were normalized to a MNI‐T2 template by an affine transformation with 12 degrees of freedom and trilinear interpolation. The spatial transformation parameters obtained from this step were applied to the free‐water maps. Finally, for each participant, ROIs corresponding to the left and right posterior substantia nigra were hand‐drawn on the normalized b0 image, and blinded to group status, and blinded to the free‐water image. High inter‐rater reliability of the posterior substantia nigra delineation on the normalized b0 images has been achieved in our previous work in parkinsonian disorders as well as healthy individuals [Ofori et al., 2015a, 2015b; Planetta et al., 2016; Vaillancourt et al., 2012]. Consistent with previous free‐water studies, we averaged free‐water across the left and right posterior substantia nigra, and used a bilateral ROI spanning the subthalamic nucleus as a control region [Ofori et al., 2015a, 2015b].

Force Data Analysis

Data analysis procedures were consistent with the methodology used in our previous work [Neely et al., 2013; Planetta et al., 2014]. Force output was filtered using a 10th order Butterworth filter with a cutoff frequency of 15 Hz, and four force‐related variables were calculated: (1) mean force during the hold period, (2) standard deviation of force (SD) during the hold period, (3) rate up—the rate of change of increasing force across the ramp period, and (4) rate down—the rate of change of decreasing force across the relaxation period (Table 1).

Statistical Analysis

χ 2 was used to assess differences between controls, PD on rasagiline, and PD not taking rasagiline in sex, handedness, hand tested (left/right, dominant/nondominant), as well as differences between the two PD groups in the more affected side, and Hoehn and Yahr score. Independent t‐tests were used to evaluate differences between PD on rasagiline and PD not taking rasagiline in disease duration, severity of motor symptoms (i.e., total MDS‐UPDRS‐III and MDS‐UPDRS‐III subscores for bradykinesia, and tested side vs. other side), and total LEDD. A multivariate analysis of covariance (MANCOVA), with sex as covariate, was used for testing group differences in age, MVC, MoCA, performance on the bimanual coordination task, free‐water from bilateral posterior substantia nigra and bilateral subthalamic nucleus. A separate MANCOVA that included sex and whether the hand tested was either the dominant or the nondominant hand was used to evaluate differences in percent signal change in the contralateral posterior putamen, contralateral angular gyrus, and force variables (i.e., mean force, SD of force, rate up, and rate down). Significant group effects were followed‐up with independent t‐tests. Furthermore, a standard linear regression was run in all PD patients (n = 34) in order to evaluate the relation between nigral free‐water and putaminal percent signal change. Finally, a multiple regression analysis using the backward elimination method was used to assess the relation between MRI measures and performance on the bimanual coordination task from the Purdue Pegboard Test. The significance level was set at P < 0.05. All P values reported in the result section of the manuscript were corrected for multiple comparisons using the Benjamini‐Hochberg false discovery rate (FDR) method [Benjamini and Hochberg, 1995].

RESULTS

Clinical and Force Data

The two PD groups did not significantly differ in disease duration, MDS‐UPDRS‐III (total score, bradykinesia and lateralized subscores), more affected side, Hoehn and Yahr score, and total LEDD (P > 0.05, Table 1). The MANCOVA analysis revealed an overall group effect (Wilks' λ = 0.573, F (24,74) = 2.97, P = 0.014). Significant between‐group differences were found for bimanual coordination (F (2,48) = 10.34, P = 0.006), with post hoc independent t‐tests showing that the two PD groups placed significantly less pegs on the pegboard with both hands working simultaneously than controls (P < 0.05). Results also showed that PD who had taken rasagiline placed significantly more pegs than PD who had not taken rasagiline (P = 0.036). There were no significant differences between the three groups in age, MVC, MoCA, handedness, and hand tested (left/right, dominant/non‐dominant) (P > 0.05, Table 1). Similarly, there were no significant differences in any of the force variables during the fMRI task (P > 0.05, Table 1).

Functional and Diffusion MRI Data

Figure 1 shows that the percent signal change in the posterior putamen and free‐water level in the posterior substantia nigra of a PD patient who had taken rasagiline were intermediate between the same measures of a healthy participant and a PD patient who had not taken rasagiline. Group level data support these results and show statistically significant between‐group differences in percent signal change in the posterior putamen, free‐water in the posterior substantia nigra, and the performance on the bimanual coordination task (Fig. 2). A significant group effect was found for putaminal percent signal change (F (2,48) = 11.58, P = 0.006), as well as for nigral free‐water (F (2,48) = 12.45, P = 0.002). Post hoc tests revealed that PD patients who had taken rasagiline had a lower percent signal change in the contralateral posterior putamen (P = 0.016) and a higher free‐water level bilaterally in the posterior substantia nigra (P = 0.030) compared with controls. PD patients who had not taken rasagiline also had a lower percent signal change in the contralateral posterior putamen (P = 0.003) and a higher free‐water level bilaterally in the posterior substantia nigra (P = 0.003) compared with controls. When comparing the two patient groups, PD who had not taken rasagiline were the most affected, having a significantly lower percent signal change (P = 0.032) and higher free‐water level (P = 0.016) than PD who had taken rasagiline. No group effects were detected for the functional and structural control ROIs (contralateral angular gyrus: P = 0.347; bilateral subthalamic nucleus: P = 0.896). Finally, a significant relation was found between functional and diffusion MRI measures within the nigrostriatal regions (F (1,33) = 4.40, P = 0.046; R 2 = 0.121). Specifically, elevated free‐water levels in the posterior substantia nigra were paired with a lower percent signal change in the contralateral posterior putamen. Finally, performance on the bimanual coordination task in PD was significantly related to free‐water in the posterior substantia nigra (F (1,33) = 4.30, P = 0.044; R 2 = 0.119), indicating that increased levels of free‐water were associated with worse performance on the task.

Figure 1.

Figure 1

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Task‐based fMRI signal in the posterior putamen contralateral to the tested hand and free‐water in the posterior substantia nigra averaged across sides, plotted for 1 control subject, 1 patient with PD taking rasagiline, and 1 patient with PD not taking rasagiline. BOLD = blood‐oxygen‐level dependent, C = contralateral, dMRI = diffusion magnetic resonance imaging, fMRI = functional magnetic resonance imaging, I = ipsilateral, PD = Parkinson's disease. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 2.

Figure 2

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Group data and statistically significant between‐group differences in: force‐related activity in the posterior putamen (A), free‐water in the posterior substantia nigra (B), and performance on the symmetric bimanual coordination task from the Purdue Pegboard Test (C). BOLD = blood‐oxygen‐level dependent, fMRI = functional magnetic resonance imaging, PD = Parkinson's disease, post = posterior, PPB = Purdue Pegboard Test, PSC = percent signal change.

DISCUSSION

Several studies have established that rasagiline is effective as monotherapy in early stage PD, as well as adjuvant therapy in more severe, levodopa‐treated PD [Chahine and Stern, 2011]. In this retrospective cross‐sectional study, we tested the hypothesis that the percent change in fMRI signal in the posterior putamen during a force production task, free‐water in the posterior substantia nigra, and performance on a bimanual coordination task would differ in PD patients chronically treated with rasagiline. The main findings support the hypothesis by demonstrating that PD who had been treated with rasagiline had a greater percent signal change in the posterior putamen, less free‐water in the posterior substantia nigra, and placed more pegs during the bimanual coordination task from the Purdue Pegboard Test than PD who had not taken rasagiline.

Prior studies using the same force control fMRI paradigm have shown reduced functional activity in the posterior putamen in PD compared with controls [Burciu et al., 2015; Neely et al., 2015; Planetta et al., 2014; Prodoehl et al., 2010; Spraker et al., 2010]. A meta‐analysis certifies this is a common finding across multiple task‐based fMRI studies, and across a wide range of motor tasks [Herz et al., 2014]. Here, we confirm previous fMRI results in PD by showing that the posterior putamen is hypoactive during force production in both PD cohorts as compared with controls, and extend the literature by showing that force‐related activity of the posterior putamen in PD patients who had taken rasagiline before testing was significantly higher than in PD patients who had not taken rasagiline or another MAO‐B inhibitor. This result is particularly interesting given that the force measures (i.e., mean force, variability of force, rate up, and rate down of force), as well as other important clinical variables (disease duration, severity of motor symptoms on the tested side and overall disease severity, cognitive status, total LEDD) did not significantly differ between the two PD groups.

The lack of a group difference in the functional activity of the angular gyrus suggests a focal effect of MAO‐B inhibitors on the fMRI signal in dopamine‐depleted regions of the basal ganglia such as the putamen. Previous studies in PD found that the fMRI response of the putamen can be modulated by acute administration of antiparkinsonian medication. In particular, it has been shown that during a bimanual motor task, the reduced motor‐related activity of the putamen in PD can be reversed with acute administration of levodopa [Kraft et al., 2009]. Importantly, the peak of levodopa‐related changes was in the dorsal, posterior portion of the putamen. An increase in the functional activity of the putamen in the “on” state as compared with the “off” state was also found during finger movements that were either externally‐triggered or self‐initiated, as well as ankle movements [Martinu et al., 2012; Schwingenschuh et al., 2013]. Although the effects of medication on the neural mechanisms underlying fMRI signal are currently unknown, our results complement these findings and suggest that rasagiline may modulate the activity of subcortical motor regions affected in PD. However, future studies that manipulate drug administration of rasagiline using a controlled, randomized design are needed in order to better test this hypothesis.

Current results also revealed a significant difference between the two PD groups in nigral free‐water. Free‐water values in the posterior substantia nigra were lower in PD who had taken rasagiline as compared with PD who had not taken rasagiline. Importantly, free‐water in the subthalamic nucleus did not differ between the two PD groups, suggesting a potential specific effect of the drug on the degenerated regions of the basal ganglia (i.e., substantia nigra). As for the mechanisms underlying the action of MAO‐B inhibitors, a 2‐week course of rasagiline in nonlesioned rats revealed an increase in striatal extracellular fluid levels of dopamine [Finberg, 2010]. This effect was attributed to an accumulation of β‐phenylethylamine, an amine known to act upon dopamine release, preventing it from getting absorbed too quickly [Finberg, 2010]. Together, these findings raise the question whether PD patients treated with rasagiline could perhaps exhibit a higher concentration of extracellular dopamine than PD patients not treated with rasagiline, and if this has any influence on the free‐water measure in the posterior substantia nigra.

Interestingly, the results of the current study also show that free‐water levels in the posterior substantia nigra in PD (n = 34) were related to percent signal change in the posterior putamen during force production, as well as performance on a bimanual task. This suggests that those PD patients with lower free‐water in the posterior substantia nigra had a higher putaminal fMRI response, and placed more pegs on the pegboard using both hands simultaneously. It is well recognized that PD patients exhibit difficulties with coordination of both symmetrical and asymmetrical bimanual movements [Wu et al., 2010]. Present results show that performance on the bimanual coordination task from the Purdue Pegboard Test was worse in the two PD groups as compared with controls. However, the PD who had taken rasagiline were less impaired, and placed significantly more pegs than the PD who had not taken rasagiline. This association between performance on a motor task that poses challenges in this patient population and chronic administration of rasagiline represents a novel finding which could help better understand the effects of rasagiline on motor functioning. Also, from a methodological standpoint, this work reinforces previous studies using free‐water diffusion MRI as a marker of nigral degeneration in PD [Ofori et al., 2015a, 2015b; Planetta et al., 2016]. Here, we present the first evidence that nigral free‐water in PD is related to motor‐related brain changes as measured by task‐based fMRI, as well as bilateral symmetrical motor skills.

Collectively, this study provides new evidence that supports the hypothesis that chronic administration of rasagiline may be reflected in functional and structural changes at the level of the nigrostrial system. However, there are certain aspects that need to be considered when interpreting the results. First, the study design was retrospective, and only offers a snapshot of the state of the basal ganglia in PD treated with rasagiline versus PD not treated with rasagiline. Present findings should be further tested in future prospective randomized controlled studies that utilize both neuroimaging outcomes along with various clinical measures to accurately assess the relation between rasagiline and the progression of PD. Here, although the severity of motor symptoms in the “off” state was similar across groups, and so was the total LEDD in each group before imaging, it cannot be ruled out that the fMRI signal in the putamen could be sensitive to residual effects of MAO‐B inhibition, and the slow recovery of MAO‐B site availability as shown in a C‐L‐deprenyl PET study in healthy individuals [Freedman et al., 2005]. However, between‐group differences in nigral free‐water suggest that rasagiline‐related effects could involve more than a residual effect of MAO‐B inhibition, because structural brain measures are less likely to change over a short period of time. In summary, multimodal neuroimaging measures such as task‐based fMRI and free‐water diffusion MRI detected differences in patients chronically treated with rasagiline, and these approaches could be useful in future prospective clinical trials evaluating the effects of antiparkinsonian drugs on the progression of PD.

Supporting information

Supporting Information

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ACKNOWLEDGMENT

The authors thank all participants for their time and commitment to this research.

Dr. Ofer Pasternak receives grant support from NIH, the Department of Defense, and the Brain and Behavior Foundation. Dr. Pasternak reports personal fees from University of Florida and Laureate Institute of Brain Research for consulting work. Dr. Nikolaus R. McFarland receives grant support from NIH. Dr. Michael S. Okun serves as a consultant for the National Parkinson Foundation. Dr. Okun has not received honoraria past >36 months, has received no personal support from industry. Dr. Okun has received royalties for publications with Demos, Manson, Amazon, Smashwords, and Cambridge (movement disorders books). Dr. Okun has participated in CME activities on movement disorders sponsored by the USF CME office, PeerView, Prime, and by Vanderbilt University. The institution and not Dr. Okun receives grants from Medtronic and ANS/St. Jude, and the PI has no financial interest in these grants. Dr. Okun has participated as a site PI and/or CO‐I for several NIH, foundation, and industry sponsored trials over the years but has not received honoraria. Dr. David E. Vaillancourt consults for projects at UT Southwestern Medical Center, University of Illinois at Chicago, and Great Lakes NeuroTechnologies. He is co‐founder of Neuroimaging Solutions, LLC. The other authors have no disclosers to report.

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