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The Cerebral Blood Flow Changes of Executive Dysfunction in Parkinson’s Disease Measured by Arterial Spin Labeling MRI at Cerebral Cortex Parcellations Obtained from Resting State fMRI

Dilek Betul Arslan¹, Sevim Cengiz¹, Ani Kicik², Emel Erdogdu^2,3, Zerrin Yildirim⁴, Zeynep Tufekcioglu⁴, Basar Bilgic⁴, Hasmet Hanagasi⁴, Aziz Mufit Ulug¹, Tamer Demiralp^2,5, Ibrahim Hakan Gurvit⁴, and Esin Ozturk-Isik¹

¹Biomedical Engineering Institute, Bogazici University, Istanbul, Turkey, ²Hulusi Behcet Life Sciences Research Center, Istanbul University, Istanbul, Turkey, ³Institute of Psychology and Cognition Research, University of Bremen, Bremen, Germany, ⁴Department of Neurology, Istanbul University, Istanbul, Turkey, ⁵Department of Physiology, Istanbul University, Istanbul, Turkey

Synopsis

The aim of this study is to find cerebral blood flow (CBF) based biomarkers of executive dysfunction in Parkinson’s disease (PD) at cerebral cortex parcellations obtained from resting state fMRI. CBF maps of PD with mild cognitive impairment, cognitively normal PD and healthy controls were compared at brain regions based on parcellations obtained from resting state fMRI. Additionally, CBF values of the PD subjects were classified according to Stroop scores and COMT genotype. Hypoperfusion in several brain networks related with executive functioning was observed in PD patients with executive dysfunction, and also in patients with COMT Met/Met genotype.

Introduction

Impairments in executive functioning are commonly observed in Parkinson's disease (PD).¹The presence of executive dysfunction in PD at early stages could be assessed by using Stroop test.² Previous studies reported that COMT Val158Met polymorphism could be related to executive dysfunction. ^3,4 There have been several studies showing the relationship of brain blood flow and executive impairment in some diseases.^5,6 Arterial spin labeling MRI (ASL-MRI) quantitatively measures cerebral blood flow (CBF) per 100 grams of tissue per minute.⁷ The main aim of this study is to assess the changes in CBF patterns of executive dysfunction in PD at its early stages in several brain regions based on parcellations obtained from resting state fMRI.

Methods

Twenty-seven PD with mild cognitive impairment (PD-MCI), 27 cognitively normal PD (PD-CN) and 15 healthy control (HC) patients, who were previously diagnosed based on an extensive neuropsychological test battery, were scanned on a 3T clinical MR scanner (Philips Medical Systems, Best, The Netherlands) with a 32-channel head coil. Single nucleotid polimorphism (SNP) genotyping for rs4680 (tagging COMT Val/Val vs Met/Met haplotype) was performed on DNA extracted from venous blood sample of all subjects by using Stratagene Mx3005p real-time PCR machine (Agilent Technologies, USA). ASL-MRI data were acquired by using STAR labeling with Look Locker sequence at eight different inversion times (TIs). ASL-MRI acquisition was repeated 30 times for each TI to increase the signal to noise (SNR). To cover the whole brain, three ASL-MRI data acquisitions including 18 slices in total were performed. An in-house program was written in MATLAB R2018a (MathWorks Inc., Natick, MA) to calculate the CBF maps. The main magnetization, M₀, was estimated for each pixel by using different TIs of the control images. CBF maps were modeled.^8,9 Afterwards, estimated CBF maps were resampled to MNI152 brain atlas by using FMRIB Software Library (FSL) (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/). Mean CBF values were calculated at 100 parcellations of cerebral cortex corresponding to 7 networks proposed by Schaefer et al. ¹⁰ The CBF values were compared between PD-MCI, PD-CN and HC by applying a Kruskal-Wallis test followed by a Tukey-Kramer post-hoc test. The CBF values of the PD patients with and without executive dysfunction, based on the median Stroop test scores, were compared by using a Mann-Whitney rank-sum test. Additionally, Mann-Whitney rank-sum test was used to assess CBF differences between PD patients with different COMT genotype.

Results

Figure 1 shows M₀ (a) and CBF (b) maps of an example HC subject. PD-CN patients had lower CBF at frontal medial cortex, which is a part of salience/ventral attention network (SalVentAttn), at right hemisphere (RH) than HC (Table 1). PD patients with executive dysfunction had decreased perfusion at lateral prefrontal cortex part of executive control network (Cont) at left hemisphere (LH), and frontal eye fields part of dorsal attention network (DorsAttn), lateral prefrontal cortex part of SalVentAttn, and lateral prefrontal cortex part of executive control network (Cont) at RH than PD patients without executive dysfunction (Table 2). CBF values of PD patients with COMT Met/Met genotype were lower at somatomotor network (SomMot) and temporal cortex (TempPar) at RH when compared to PD patients with COMT Val/Val genotype (Table 3).

Discussion

It has been reported that poor performance on cognitive tests was correlated with decreased metabolic activity in prefrontal cortex and medial frontal cortex.¹¹ Medial frontal cortex is responsible for action monitoring, response conflict, reward and decision-making.¹²Lateral prefrontal cortex plays a role in executive behavioral control.¹³ Hypoperfusion at lateral prefrontal cortex and medial frontal cortex might be related to executive dysfunction in decision-making system and response to conflict, because these brain regions were defined as parts ofSalVentAttn at RH. Moreover, decreased perfusion at lateral preforantal cortex part of Cont network in PD with executive impairment might cause problems in controlling cognitive behaviors. Because the neurons in frontal eye fields have a decisive role in saccade programming as a part of DorsAttn, PD patients with executive impairment might have problems in gaze.¹⁴ High COMT enzyme activity has been associated with cognitive impairment in PD patients.¹⁵ The higher COMT enzyme at temporal and somatomotor network might be associated with lower perfusion and spatial awareness in PD.

Conclusion

Future studies will include partial volume correction to estimate pure gray matter perfusion.¹⁶ Our study results indicated that CBF values of PD patients might aid in assessment of executive deficits and might be used as a biomarker for identifying the disease severity in PD.

Acknowledgements

This study was supported by TUBITAK project #115S219 and the Ministry of Development project #2010K120330.

References

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Figures

Figure 1.The M₀ and CBF maps of an example HC subject.

Table 1. Mean (±std) CBF values of subjects at right hemisphere, salience/ventral attention network, frontal medial cortex and P values calculated by using a Kruskal-Wallis test and Tukey-Kramer post-hoc test (*P<0.05)

Table 2. Mean (±std) CBF values of PD subjects with and without executive dysfunction at several brain regions of resting state fMRI networks and P values calculated by Mann-Whitney rank-sum test. (*P<0.05)

Table 3. The mean (±std) CBF values of HC, PD-MCI and PD-CN patients having different COMT genotypes at several brain regions defined by resting state fMRI networks and P values calculated by Mann-Whitney rank-sum test. (*P<0.05)

Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)

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