Abnormal white matter microstructure in Parkinson’s disease revealed by diffusion tensor imaging A non-randomized concurrent control observation*☆
Jiangtao Liu1, 2, Kuncheng Li1, 2, Jinglin Zhang2, Xiaoli Wu2, Biao Chen2

1Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing  100053, China
2Key Laboratory of Ministry of Education on Neurodegenerative Diseases, Xuanwu Hospital, Capital Medical University, Beijing  100053, China

Jiangtao Liu☆, Doctor, Attending physician, Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; Key Laboratory of Ministry of Education on Neurodegenerative Diseases, Xuanwu Hospital, Capital Medical University, Beijing  100053, China
liujiangtao0813@sina.com

Corresponding author: Kuncheng Li, Doctor, Professor, Chief physician, Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China; Key Laboratory of Ministry of Education on Neurodegenerative Diseases, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
likuncheng1955@yahoo. com.cn

Supported by: the National Natural Science Foundation of China, No. 30770620*

Abstract
BACKGROUND: Imaging has been used to determine gray matter volume and metabolism in subjects with depressed Parkinson’s disease (DPD).
OBJECTIVE: To reveal abnormalities in orbitofrontal white matter and the anterior cingulate bundle in depressed and non-depressed Parkinson’s disease (NDPD) patients using diffusion tensor im-aging.
DESIGN, TIME AND SETTING: A non-randomized, concurrent, control, neuroimaging study was performed at the Laboratory of Neurodegenerative Diseases and Center of Neuroimage, Xuanwu Hospital of Capital Medical University from July 2008 to January 2009.
PARTICIPANTS: A total of 30 Parkinson’s disease patients, including 14 males and 16 females, were included in the present study. All patients met Brain Bank criteria for idiopathic Parkinson’s disease formulated by the United Kingdom Parkinson’s Disease Society. Patients, who underwent previous head surgery, exhibited abnormal density on T2-weighted images, or Mini-Mental State Examination scores < corresponding education level, were excluded from the study.
METHODS: All 35 patients underwent MRI scans, including traditional T2-weighted and DTI scans. The patients were assigned to DPD (n = 16) and NDPD (n = 14) groups according to the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria. The fractional anisotropy values of regions of interest were compared between the NDPD and DPD groups.
MAIN OUTCOME MEASURES: Abnormalities in the orbitofrontal white matter and anterior cingu-late bundle.
RESULTS: Compared with the NDPD group, the DPD group exhibited significantly lower fractional anisotropy values in orbitofrontal white matter and anterior cingulate bundle (P < 0.05).
CONCLUSION: Microstructure abnormalities existed in the orbitofrontal and anterior cingulate re-gions in DPD patients. This is the first report of abnormalities in the orbitofrontal white matter region in DPD patients.
Key Words: Parkinson’s disease; depression; diffusion tensor imaging; fractional anisotropy

INTRODUCTION
  
The pathophysiology of depressed Parkinson’s disease (DPD) remains uncertain. It remains to be determined whether depression in Parkinson’s disease is a result of pathological mechanisms similar to de novo depression or to non-depressed Parkinson’s disease (NDPD).
Depression is postulated to be a result of connectivity imbalances in the mood regulating circuit, which leads to decreased regulation of cortical areas over limbic regions[1-2]. Studies have implicated the orbitofrontal cortex and anterior cingulate cortex in the production of affective states in humans[3-4]. The orbitofrontal cortex and anterior cingulate cortex are included in the dorsal nervous system and have been implicated in performance of cognitive tasks and regulation of affective states[5]. Reduced volume[6-10] and dysfunction[11-12] in the orbitofrontal cortex have been shown in several forms of depressive disorders. Studies have also revealed decreased activation in the anterior cingulate cortex[5] and decreased connectivity in the anterior cingulate cortex-limbic circuit in major depressive disorder[13].
Diffusion tensor imaging has allowed for the estimation of neuronal changes in live patients with neurological diseases by monitoring fractional anisotropy values[14]. While fractional anisotropy reductions in the prefrontal region[15] and anterior cingulate region[16] have been reported in de novo 
 
depression, few imaging studies have documented depression in Parkinson’s disease.
The present study utilized diffusion tensor imaging to reveal abnormalities in the orbitofrontal white matter and anterior cingulate bundles in NDPD and DPD patients to determine microstructural changes of depression in Parkinson’s disease.

SUBJECTS AND METHODS

Design
A non-randomized, concurrent, controlled, neuroimaging study.
Time and setting
This study was performed at the Laboratory of Neurodegenerative Diseases and Center of Neuroimaging, Xuanwu Hospital of Capital Medical University from July 2008 to January 2009.
Subjects
A total of 30 patients, diagnosed with idiopathic Parkinson’s disease and without a history of other neurological illnesses or any contraindications for MRI, were recruited for the study. All patients met the Brain Bank criteria for idiopathic Parkinson’s disease formulated by the United Kingdom Parkinson’s Disease Society[17]. Motor and mental states were evaluated by Unified Parkinson’s Disease Rating Scale motor score (UPDRS III)[18], Hoehn-Yahr stage (H-Y)[18], and Mini-Mental State Examination (MMSE)[19]. Depression diagnosis was made using the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria[20]. The Hamilton Depression Scale (HAMD) was also implemented[21]. Patients, who had undergone previous head surgery or exhibited abnormal density on T2-weighted brain MR images, were excluded. Patients with MMSE scores < the corresponding education level were also excluded. The patients were then assigned to DPD (n = 16) and NDPD (n = 14) groups according to DSM-IV criteria. All clinical evaluation was performed by two experienced neurologists. Study content was reviewed by the ethics committee of Xuanwu Hospital and all patients provided informed consent prior to inclusion into the study.
Methods
MRI scanning procedures
Magnetic resonance imaging was acquired using a 3.0-T imager (TrioTim, Siemens Medical Solutions, Erlangen, Germany). In addition to conventional T2-FLAIR images (TR/TE = 9 000 ms/128 ms, TI = 2 500 ms) to exclude clinically significant abnormalities, diffusion tensor images were obtained using the following sequence: field of view = 256 mm × 100 mm; matrix = 128 × 100; TR/TE = 6 000 ms/93 ms; flip angle = 90; b values = 0 and       1 000 s/mm2; and slice/gap = 4/0 mm. All scans were performed parallel to the anterior-posterior commissure. Diffusion sensitization was applied in 20 directions. Acquisition time for diffusion tensor imaging was 6' 38''.
Images were exported from the MRI unit to an offline computer workstation (Syno MMWP VE26A Leonardo). Offline tensor calculation and Neuro3D was used for FA measurements. Regions of interest located in the bilateral orbitofrontal white matter and anterior cingulate bundle were set for both groups on the b0 image, and the fractional anisotropy value was automatically listed. The region of interest diameter was set to 10 mm. Cortex and fluid contamination was avoided. All evaluations were carried out blindly by an experienced neuroradiologist. The regions of interest are shown in Figure 1. The fractional anisotropy value of regions of interest between NDPD and DPD was compared.

Main outcome measures
ROI of the orbitofrontal white matter and anterior cingulate bundle was made, and the FA value of ROIs between NDPD and DPD was compared.
Design, enforcement, and evaluation
This study was designed and conducted by all authors and evaluated by a radiologist using blinded methodology.
Statistical analysis
Data analysis and statistics were performed using SPSS for Windows 10.0 (SPSS, IL, Chicago, USA). Independent sample t-test was used to analyze differences between clinical data from depressed and non-depressed groups. A significance level was set to P < 0.05.

RESULTS

Quantitative analysis of participants
Thirty patients were included in the final analysis.
Clinical profiles of included patients
There were no significant differences with respect to patient clinical profiles between the two groups except for HAMD scores (P > 0.05, Table 1). 

Fractional anisotropy value of bilateral orbitofrontal and anterior cingulate bundle regions of interest
Statistical analysis showed that, compared with NDPD, patients with DPD exhibited significantly lower fractional anisotropy values in orbitofrontal white matter and anterior cingulate bundle (P < 0.05, Table 2).

DISCUSSION

Reduced fractional anisotropy values were observed in regions representing bilateral orbitofrontal fibers and the anterior cingulate bundle in DPD compared with NDPD. This result was consistent with a previous metabolism study of DPD, which reported selective hypometabolism in the inferior frontal lobe[22], orbitofrontal, and anterior cingulate cortices of depressed Parkinson’s disease patients[13, 23-24]. Left-sided orbitofrontal and bilateral rectal gyrus density changes in depressed patients with Parkinson’s disease[25] were also reported. Few imaging studies have used diffusion tensor imaging to identify the microstructure of DPD. A study recently compared DPD and NDPD patients and determined reduced fractional anisotropy values in the bilateral anterior cingulate bundles in DPD patients, but no significant differences in fractional anisotropy values in other regions, including the orbitofrontal white matter[26]. This was inconsistent with the present results, which could be due to sample characteristics and number of samples. Therefore, whole-brain analysis is needed to clarify these differences.
The medial prefrontal lobe plays a role in automatic regulation of emotional behavior, and impairments are hypothesized to be most strongly associated with cognitive and emotional dysfunction in depression[27-29]. The decreased regulatory effect of cortical regions over the limbic regions explained emotional dysregulation in the depressed state. In addition, decreased fractional anisotropy values within orbitofrontal fibers and anterior cingulate bundle in DPD patients suggested impaired fibers in these regions, which was consistent with previous hypotheses of cortical-limbic dysregulation in depressive disorder[5].
Several limitations must be considered when evaluating the findings. First, although statistically significant group differences were observed, the patient sample size was relatively small, and the power to assess these result was, therefore, not ideal. Second, although patients in this study were not medicated with psychotropic medications until time of scanning, potential drug interference cannot be entirely eliminated. There is increasing evidence that some psychotropic medications may alter brain structure, function, and chemistry[30]. Third, the present study utilized regions of interest-based techniques, which were dependent on previous assumptions of region size and shape to be evaluated. Focal abnormalities other than orbitofrontal fiber tract and anterior cingulate bundle abnormalities were, therefore, not identified. To avoid this, voxel-based analysis of fractional anisotropy evaluation, which remains independent of previous assumptions of brain areas of potential interests, may provides a means to objectively localize focal changes of voxel values throughout the entire brain volume[31].
In summary, the present findings demonstrated that patients with DPD exhibited lower fractional anisotropy values in the bilateral orbitofrontal tract and anterior cingulate regions compared with NDPD patients. These results suggested that microstructure abnormalities exist in regions of mood regulation in DPD patients, which could partially explain depressive symptoms in Parkinson’s disease groups.

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 (Edited by Yan LR/Ji H/Song LP)