Voxel-Based Analysis of Brain Microstructural Diffusion Indices Changes in Parkinson Disease with Freezing of Gait
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms such as bradykinesia, tremor, and rigidity. However, non-motor symptoms, including cognitive impairment and freezing of gait (FOG), also significantly impact patients’ quality of life. FOG is a particularly disabling movement disorder that affects approximately 50% to 80% of PD patients in the later stages of the disease. It is characterized by sudden, brief episodes during which patients are unable to initiate or continue walking, often leading to falls and severe physical and emotional consequences. Unlike other motor symptoms of PD, FOG is often resistant to dopaminergic medication therapy and may even worsen with levodopa treatment. This suggests that FOG may involve mechanisms beyond pure motor dysfunction, potentially implicating cognitive impairment. Recent studies have shown that cognitive training can reduce the severity of FOG, further supporting the hypothesis that cognitive dysfunction plays a role in its pathophysiology.
To investigate the relationship between cognitive impairment and FOG in PD, this study employed voxel-based analysis (VBA) of diffusion tensor imaging (DTI) data to examine changes in brain microstructural diffusion indices in PD patients with FOG (FOG+), PD patients without FOG (FOG–), and healthy controls (HCs). The study aimed to identify specific brain regions where microstructural changes might be associated with FOG and cognitive dysfunction.
Study Design and Participants
The study recruited 20 FOG+ patients from the Department of Neurology at Guangdong Provincial People’s Hospital between January 2014 and December 2016. Additionally, 23 FOG– patients and 20 age-, sex-, and education-level-matched HCs were selected from the hospital’s PD research database. All participants provided written informed consent, and the study was approved by the Institutional Ethics Committee of Guangdong Provincial People’s Hospital. All subjects were right-handed, as determined by the Edinburgh Handedness Inventory.
PD patients were diagnosed according to the UK Brain Bank criteria by two experienced neurologists. Clinical assessments were conducted in the “off” medication state, defined as 12 hours after withdrawal of anti-Parkinsonian medication. Disease severity was evaluated using the Hoehn and Yahr staging (H-Y), while global cognitive function was assessed with the Mini-Mental State Examination (MMSE). Motor symptom severity was measured using the Unified Parkinson Disease Rating Scale (UPDRS)-III. FOG+ patients were identified based on a score of ≥1 on item 3 of the FOG Questionnaire and either or both of the following criteria: (a) the participant’s verbal account of experiencing FOG, and (b) the patient’s recognition of typical FOG when described by an experienced neurologist. Patients who did not meet these criteria were classified as FOG–.
Imaging Data Acquisition and Analysis
DTI data were collected using a 3.0T MRI scanner (Signa Excite HD, GE Healthcare, Milwaukee, WI, USA). The data were pre-processed using the Pipeline for Analyzing braiN Diffusion imAges (PANDA) software package, which is based on MATLAB R2012a. Statistical analyses of clinical data were performed using SPSS 21.0 software, with significance set at P < 0.05. The exclusion criteria for all subjects and detailed neuroimaging analysis methods are provided in the Supplementary Materials.
Clinical and Demographic Characteristics
No significant differences were observed among FOG+ patients, FOG– patients, and HCs in terms of age, sex, or education level. However, FOG+ patients had significantly lower MMSE scores (P < 0.05) and significantly higher UPDRS-III (P < 0.05) and H-Y scores (P < 0.05) compared to FOG– patients. The mean disease duration was also significantly longer in FOG+ patients than in FOG– patients (P < 0.05).
Diffusion Indices Analysis
The analysis of diffusion indices revealed significant differences in mean diffusivity (MD) values between FOG+ and FOG– patients. Specifically, MD values were significantly higher in the frontal lobe (including the bilateral medial frontal gyrus, right superior frontal gyrus, bilateral inferior frontal gyrus, right middle frontal gyrus, and pre-central gyrus), limbic areas (including the hook, right amygdala, bilateral parahippocampal gyrus, hippocampus, and cingulate gyrus), and bilateral temporal lobe (including the right middle temporal gyrus, left inferior temporal gyrus, and bilateral superior temporal gyrus) in FOG+ patients compared to FOG– patients. In contrast, no significant differences were observed in fractional anisotropy (FA) values between these groups, except for reduced FA values in the left insula of FOG+ patients.
When comparing FOG+ patients to HCs, higher MD values were also observed in the frontal lobe, but no significant changes were found between FOG– patients and HCs. These findings suggest that FOG+ patients exhibit distinct microstructural changes in brain regions associated with cognitive function.
Discussion
The primary finding of this study is that FOG+ patients exhibit impaired cognitive function and microstructural changes in the bilateral frontal lobe. The lower MMSE scores in FOG+ patients compared to FOG– patients indicate that cognitive impairment is more pronounced in this group. The higher MD values in the frontal lobe, as identified by VBA, further support the hypothesis that cognitive dysfunction plays a critical role in the pathophysiology of FOG. MD is a measure of average molecular motion and reflects microstructural changes in neural tissue. The observed increase in MD values in the frontal lobe suggests that this region may be particularly vulnerable to neurodegeneration in FOG+ patients.
The frontal lobe is known to play a central role in executive functions, including cognitive flexibility, attention, and motor planning. Impairments in these cognitive domains are widely recognized as a “cognitive signature” associated with FOG. Previous functional MRI studies have also reported abnormal activation and connectivity in brain regions responsible for frontal executive and attention abilities in FOG+ patients. The findings of this study align with these observations, emphasizing the importance of frontal lobe dysfunction in the development of FOG in PD patients. Specifically, the dysfunction of the frontal lobe may lead to a decreased ability to focus attention on motor performance, resulting in FOG episodes.
In addition to the frontal lobe, this study identified significant microstructural changes in limbic areas and the temporal lobe in FOG+ patients. The limbic system, which includes structures such as the amygdala, hippocampus, and cingulate gyrus, is involved in emotional regulation and memory. Decreased dopamine levels in the limbic system have been associated with pathological changes in PD. Mood disorders, which are often linked to limbic system dysfunction, are more common in FOG+ patients and are positively correlated with the severity of cognitive impairment. These findings suggest that dysfunctional limbic areas may also contribute to the occurrence of FOG in PD.
The temporal lobe, particularly the middle temporal gyrus and inferior temporal gyrus, was also affected in FOG+ patients. Recent evidence indicates that visuospatial integration, which is associated with the middle temporal area, is more severely impaired in FOG. This suggests that temporal lobe dysfunction may further exacerbate the cognitive and motor deficits observed in FOG+ patients.
Conclusion
This study provides compelling evidence that FOG+ patients exhibit impaired cognitive function and microstructural changes in brain regions associated with cognition, particularly the frontal lobe. The findings highlight the importance of frontal lobe dysfunction in the pathophysiology of FOG and support the use of cognitive training as a therapeutic intervention for FOG+ patients. Additionally, the involvement of limbic and temporal lobe areas underscores the complex interplay between cognitive and motor dysfunction in PD.
The results of this study contribute to a deeper understanding of the neural mechanisms underlying FOG in PD and may guide the development of targeted therapies to improve the quality of life for patients with this debilitating condition.
doi.org/10.1097/CM9.0000000000001042
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