Allelic variant in SLC6A3 rs393795 affects cerebral regional homogeneity and gait dysfunction in patients with Parkinson’s disease

Aims We sought to explore the role of the SLC6A3 rs393795 allelic variant in cerebral spontaneous activity and clinical features in Parkinson’s disease (PD) via imaging genetic approach. Methods Our study recruited 50 PD and 45 healthy control (HC) participants to provide clinical, genetic, and resting state functional magnetic resonance imaging (rs-fMRI) data. All subjects were separated into 16 PD-AA, 34 PD-CA/CC, 14 HC-AA, and 31 HC-CA/CC four subgroups according to SLC6A3 rs393795 genotyping. Afterwards, main effects and interactions of groups (PD versus HC) and genotypes (AA versus CA/CC) on cerebral function reflected by regional homogeneity (ReHo) were explored using two-way analysis of covariance (ANCOVA) after controlling age and gender. Finally, Spearman’ s correlations were employed to investigate the relationships between significantly interactive brain regions and clinical manifestations in PD subgroups. Results Compared with HC subjects, PD patients exhibited increased ReHo signals in left middle temporal gyrus and decreased ReHo signals in left pallidum. Compared with CA/CC carriers, AA genotype individuals showed abnormal increased ReHo signals in right inferior frontal gyrus (IFG) and supplementary motor area (SMA). Moreover, significant interactions (affected by both disease factor and allelic variation) were detected in right inferior temporal gyrus (ITG). Furthermore, aberrant increased ReHo signals in right ITG were observed in PD-AA in comparison with PD-CA/CC. Notably, ReHo values in right ITG were negatively associated with Tinetti Mobility Test (TMT) gait subscale scores and positively related to Freezing of Gait Questionnaire (FOG-Q) scores in PD-AA subgroup. Conclusions Our findings suggested that SLC6A3 rs393795 allelic variation might have a trend to aggravate the severity of gait disorders in PD patients by altering right SMA and IFG function, and ultimately result in compensatory activation of right ITG. It could provide us with a new perspective for exploring deeply genetic mechanisms of gait disturbances in PD.

Download Full-text

Alterations of regional homogeneity in freezing of gait in Parkinson's disease

Journal of the Neurological Sciences ◽

10.1016/j.jns.2018.01.021 ◽

2018 ◽

Vol 387 ◽

pp. 54-59 ◽

Cited By ~ 6

Author(s):

Caihong Zhou ◽

Xiaoling Zhong ◽

Yongzhe Yang ◽

Wanqun Yang ◽

Lijuan Wang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Freezing Of Gait ◽

Regional Homogeneity

Download Full-text

The Association between DRD3 Ser9Gly Polymorphism and Depression Severity in Parkinson’s Disease

Parkinson s Disease ◽

10.1155/2019/1642087 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Yan Zhi ◽

Yongsheng Yuan ◽

Qianqian Si ◽

Min Wang ◽

Yuting Shen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Resting State ◽

Brain Function ◽

Clinical Manifestations ◽

Brain Regions ◽

Potential Effect ◽

Analysis Of Covariance ◽

Significant Difference ◽

The Right

More and more evidence suggests that dopamine receptor D3 gene (DRD3) plays an important role in the clinical manifestations and the treatment of Parkinson’s disease (PD). DRD3 Ser9Gly polymorphism is the most frequently studied variant point. Our aim was to investigate the potential effect of DRD3 Ser9Gly polymorphism on modulating resting-state brain function and associative clinical manifestations in PD patients. We consecutively recruited 61 idiopathic PD patients and 47 healthy controls (HC) who were evaluated by clinical scales, genotyped for variant Ser9Gly in DRD3, and underwent resting-state functional magnetic resonance imaging. Based on DRD3 Ser9Gly polymorphism, PD patients and HCs were divided into four subgroups. Then, two-way analysis of covariance (ANCOVA) was applied to investigate main effects and interactions of PD and DRD3 Ser9Gly polymorphism on the brain function via amplitude of low-frequency fluctuations (ALFF) approach. The association between DRD3 Ser9Gly-modulated significantly different brain regions, and clinical manifestations were detected by Spearman’s correlations. PD patients exhibited decreased ALFF values in the right inferior occipital gyrus, lingual gyrus, and fusiform gyrus. A significant difference in the interaction of “groups × genotypes” was observed in the right medial frontal gyrus. The ALFF value of the cluster showing significant interactions was positively correlated with HAMD-17 scores (r=0.489, p=0.011) and anhedonia scores (r=0.512, p=0.008) in PD patients with the Ser/Gly or Gly/Gly genotypes. Therefore, D3 gene Ser9Gly polymorphism might be associated with the severity of depression characterized by anhedonia in PD patients.

Download Full-text

Alterations of Regional Homogeneity in Parkinson’s Disease Patients With Freezing of Gait: A Resting-State fMRI Study

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2019.00276 ◽

2019 ◽

Vol 11 ◽

Cited By ~ 1

Author(s):

Yanjun Liu ◽

Mengyan Li ◽

Haobo Chen ◽

Xinhua Wei ◽

Guihe Hu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Resting State ◽

Freezing Of Gait ◽

Resting State Fmri ◽

Regional Homogeneity ◽

Fmri Study

Download Full-text

Wearable Sensors System for an Improved Analysis of Freezing of Gait in Parkinson’s Disease Using Electromyography and Inertial Signals

Sensors ◽

10.3390/s19040948 ◽

2019 ◽

Vol 19 (4) ◽

pp. 948 ◽

Cited By ~ 16

Author(s):

Ivan Mazzetta ◽

Alessandro Zampogna ◽

Antonio Suppa ◽

Alessandro Gumiero ◽

Marco Pessione ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Fall Risk ◽

Wearable Sensors ◽

Freezing Of Gait ◽

Clinical Manifestations ◽

Leg Muscles ◽

Trunk Inclination ◽

First Time ◽

Underlying Pathophysiology

We propose a wearable sensor system for automatic, continuous and ubiquitous analysis of Freezing of Gait (FOG), in patients affected by Parkinson’s disease. FOG is an unpredictable gait disorder with different clinical manifestations, as the trembling and the shuffling-like phenotypes, whose underlying pathophysiology is not fully understood yet. Typical trembling-like subtype features are lack of postural adaptation and abrupt trunk inclination, which in general can increase the fall probability. The targets of this work are detecting the FOG episodes, distinguishing the phenotype and analyzing the muscle activity during and outside FOG, toward a deeper insight in the disorder pathophysiology and the assessment of the fall risk associated to the FOG subtype. To this aim, gyroscopes and surface electromyography integrated in wearable devices sense simultaneously movements and action potentials of antagonist leg muscles. Dedicated algorithms allow the timely detection of the FOG episode and, for the first time, the automatic distinction of the FOG phenotypes, which can enable associating a fall risk to the subtype. Thanks to the possibility of detecting muscles contractions and stretching exactly during FOG, a deeper insight into the pathophysiological underpinnings of the different phenotypes can be achieved, which is an innovative approach with respect to the state of art.

Download Full-text

Deep brain stimulation of the Cuneiform nucleus for levodopa-resistant freezing of gait in Parkinson’s disease: study protocol for a prospective, pilot trial

Pilot and Feasibility Studies ◽

10.1186/s40814-021-00855-7 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Stephano J. Chang ◽

Iahn Cajigas ◽

James D. Guest ◽

Brian R. Noga ◽

Eva Widerström-Noga ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Deep Brain Stimulation ◽

Pilot Study ◽

Brain Stimulation ◽

Freezing Of Gait ◽

Mesencephalic Locomotor Region ◽

Link Type ◽

Cuneiform Nucleus ◽

Deep Brain

Abstract Background Freezing of gait (FOG) is a particularly debilitating motor deficit seen in a subset of Parkinson’s disease (PD) patients that is poorly responsive to standard levodopa therapy or deep brain stimulation (DBS) of established PD targets such as the subthalamic nucleus and the globus pallidus interna. The proposal of a DBS target in the midbrain, known as the pedunculopontine nucleus (PPN) to address FOG, was based on its observed pathology in PD and its hypothesized involvement in locomotor control as a part of the mesencephalic locomotor region, a functionally defined area of the midbrain that elicits locomotion in both intact animals and decerebrate animal preparations with electrical stimulation. Initial reports of PPN DBS were met with much enthusiasm; however, subsequent studies produced mixed results, and recent meta-analysis results have been far less convincing than initially expected. A closer review of the extensive mesencephalic locomotor region (MLR) preclinical literature, including recent optogenetics studies, strongly suggests that the closely related cuneiform nucleus (CnF), just dorsal to the PPN, may be a superior target to promote gait initiation. Methods We will conduct a prospective, open-label, single-arm pilot study to assess safety and feasibility of CnF DBS in PD patients with levodopa-refractory FOG. Four patients will receive CnF DBS and have gait assessments with and without DBS during a 6-month follow-up. Discussion This paper presents the study design and rationale for a pilot study investigating a novel DBS target for gait dysfunction, including targeting considerations. This pilot study is intended to support future larger scale clinical trials investigating this target. Trial registration ClinicalTrials.gov identifier: NCT04218526 (registered January 6, 2020)

Download Full-text