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Keywords:

  • Parkinson's disease;
  • local gyrification index;
  • cortical gyrification;
  • white matter connectivity;
  • intracortical organization

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Financial Disclosures
  7. References
  8. Supporting Information

Background

Parkinson's disease (PD) is a neurodegenerative disorder characterized by both motor and non-motor symptoms. Previous morphometric studies of PD were mainly conducted by measuring gray matter volume and cortical thickness, and little attention has been paid to the morphology of the cortical surface.

Methods

Using a surface-based local gyrification index (lGI), this study compared the cortical gyrification patterns of 37 PD patients and 34 matched healthy controls. Volumetric analyses also were performed on the subcortical structures.

Results

Compared with the control group, patients with PD had significantly reduced cortical gyrification in multiple brain regions, which the authors speculated were associated with disruptions in white matter connectivity and suboptimal intracortical organization. In addition, subcortical volume atrophy was identified in the bilateral hippocampus and bilateral caudate of the patients with PD.

Conclusions

Further studies are needed to identify the clinical correlates of the structural abnormalities observed in PD. © 2013 International Parkinson and Movement Disorder Society

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non-motor symptoms.[1] Many symptoms of PD are thought to be associated with neuropathological changes in extranigral regions.[2] Moreover, postmortem studies have shown that the pathology of PD gradually spreads from subcortical structures to the limbic cortices and eventually to the neocortex, leading to structural abnormalities.[3] Quantitative evaluations of cortical and subcortical abnormalities in PD may provide new insights into the pathogenesis of this disorder.

Since the advent of magnetic resonance imaging (MRI), various morphometric approaches have been developed to identify macroscopic changes in the human brain. To date, the majority of morphometric studies of PD have been conducted using voxel-based morphometry (VBM).[4-6] However, the specific contribution of the anatomic properties of the cortical mantle to VBM results remains unknown.[7] Studies measuring gray matter thickness have reported significant cortical thinning in PD,[8, 9] whereas little attention has been paid to the morphology of the cortical surface.

Cortical gyrification, the process by which the cortical surface morphology is altered to create the sulcal and gyral regions,[10] is thought to reflect both interregional connectivity[11, 12] and optimal intracortical organization,[13] with the most axonal connections in the least possible volume.[14] The local gyrification index (lGI), a new surface-based measurement of cortical gyrification, is able to identify region-specific changes in cortical gyrification and to measure the spatial frequency of cortical gyrification and the depth of the sulci.[15] In previous neuroimaging investigations, the lGI was used successfully to study the morphology of cortical gyrification in conditions such as depression,[16] schizophrenia[17, 18] and 22q11 deletion syndrome.[19, 20]

Therefore, in this study, we used the lGI to investigate the pattern of cortical gyrification in PD patients compared with matched controls. We compared the lGI results from controls and patients with PD using a surface-based general linear model (GLM) to map group contrasts on a vertex-by-vertex basis. We also performed volumetric analyses on the subcortical structures. Based on the existing literature,[21, 22] we hypothesized that patients with PD would exhibit structural abnormalities in both cortical and subcortical regions, including the frontal and temporal cortices and the basal ganglia.

Patients and Methods

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Financial Disclosures
  7. References
  8. Supporting Information

Patients

Thirty-seven patients who had PD without dementia and 34 controls were included in the study. The clinical diagnosis of PD was confirmed according to UK Parkinson's Disease Society Brain Bank criteria.[23] All participants underwent extensive neurologic, neuropsychological, and clinical imaging examinations. Participants who had a history of neurologic or psychiatric disease or neurologic sequelae induced by brain trauma were excluded. Movement symptom severity was assessed using the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS-III) after overnight withdrawal from medication and within 1 week post-MRI scan examination.[24] Detailed demographic data are provided in Supporting Table 1 in the Supplementary Materials. This study was approved by the institutional review board, and written informed consent was obtained from all participants.

Table 1. Regions that had reduced cortical gyrification in patients with Parkinson's disease versus controls
Anatomic RegionSideCluster Size, No. of VerticesControlsPD PatientsPercentage ReductionPPeak Coordinates: x, y, x
  1. Abbreviations: PD, Parkinson's disease.

Inferior parietal cortexLeft9273.12 (0.12)3.01 (0.12)3.70.0339−43.2, −74.5, 24.4
Lingual and fusiform gyrus, parahippocampal gyrus, entorhinal cortexLeft32332.70 (0.12)2.61 (0.11)3.50.0048−26.2, −56.4, −9.72
Lateral orbitofrontal cortexLeft1612.36 (0.11)2.27 (0.10)4.10.0432−18,9, 8.23, −21.0
Superior and middle temporal gyrusRight25434.04 (0.34)3.80 (0.21)5.80.002663.1, −19.0, −3.97

MRI Data Acquisition

MRI scans were performed using a Siemens Trio 3.0-T scanner (Siemens Medical Solutions, Erlangen, Germany) with a magnetization-prepared, rapid acquisition gradient-echo protocol. Detailed scan parameters were as follows: repetition time = 2000 msec; echo time = 2.6 msec; slice thickness = 1 mm; no gaps; flip angle = 9 degrees; matrix = 256 × 224; field of view = 256 × 224 mm2; 1 × 1 mm2 in-plane resolution.

Preprocessing

Each scan was processed using the FreeSurfer image analysis suite, which is documented and freely available online (http://surfer.nmr.mgh.harvard.edu/), to obtain the lGI. Briefly, the lGI map is obtained in four steps: First, the pial surface is reconstructed in 3-dimensional space. Second, the outer surface is obtained from the outer hull, which tightly wraps the pial surface. Third, the lGI is calculated for each vertex on the outer surface as a ratio of areas of circular region centered on this vertex and the area of the corresponding region of the pial surface. Thus, the lGI can be used to quantify the amount of cortical surface invaginated in the sulci and to measure the spatial frequency of the cortical gyrification and the depth of the sulci. Fourth, the lGI map is obtained by propagating the lGI values from the outer surface to the pial surface. For comparison, all of the individual reconstructed cortical surfaces were aligned to an average template using a surface-based registration algorithm.[25] Then, the lGI maps were resampled and smoothed with a heat kernel with a width of 10 mm. The volumes of all subcortical structures (thalamus, hippocampus, amygdala, putamen, globus pallidus, caudate, and accumbens) were extracted using the automated procedure for volumetric measurements of brain structures implemented in FreeSurfer.[26]

Statistical Analyses

Vertex-by-vertex contrasts of the lGI were performed to compare the controls and PD patients using the SurfStat software package (a MATLAB toolbox [MathWorks, Natick, Mass, USA]; available at: http://www.math.mcgill.ca/keith/surfstat/). Specifically, each contrast was entered into a vertex-by-vertex GLM with diagnosis, sex, age, and intracranial volume as covariates. Subsequently, a corrected cluster-wise P value was obtained using random field theory.[27] The level of significance for vertices was set at a surface-wide P < 0.05 after correction for multiple comparisons. For each subcortical structure, the GLM used in the vertex-wise analysis was fitted to test for volume differences between PD patients and controls.

Results

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Financial Disclosures
  7. References
  8. Supporting Information

Compared with controls, PD patients exhibited significant reductions in the lGI in multiple brain regions. We identified four clusters of differences with thresholds of P < 0.05 (Table 1). These clusters covered the left inferior parietal cortex, the parahippocampal gyrus, the entorhinal cortex, the lingual and fusiform gyri, the orbitofrontal cortex, and the right superior and middle temporal gyri (Fig. 1).

image

Figure 1. These images illustrate brain regions that had reductions in cortical gyrification in patients with Parkinson's disease. The results were corrected for multiple comparisons (P < 0.05; cluster-based random field theory correction). The color bar indicates corrected P values. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Subcortically, we observed significant atrophy in the bilateral hippocampus and in the left caudate and a trend toward atrophy in the right caudate in patients with PD (see Supporting Table 2 in Supporting Materials). No significant volume differences were observed in other subcortical structures.

Discussion

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Financial Disclosures
  7. References
  8. Supporting Information

In the present study, we examined the differences in cortical gyrification between patients with PD and matched controls. We identified significant lGI reductions in the left inferior parietal cortex, the parahippocampal gyrus, the entorhinal cortex, the lingual and fusiform gyri, the orbitofrontal cortex, and the right superior and middle temporal gyri in patients with PD. Subcortical atrophy was identified in the bilateral hippocampus and bilateral caudate.

Our finding of cortical gyrification reductions and subcortical atrophy in PD is partially supported by previous studies. Indeed, several morphometric studies have reported that patients with PD had decreased gray matter volume and thickness in regions in which reduced cortical gyrification was observed.[4-6, 8, 28] However, a previous study reported an increased local surface area on the intermediate surface between the gray and white matter surfaces in PD patients.[29] This result does not contradict our findings, because those indices were measured for two different surfaces. Furthermore, the results obtained from surface area measurements could be confounded by brain size, because larger brains tend to have larger surface areas. Subcortically, both global and regional atrophy in the caudate and hippocampus also have been documented in PD.[4, 6, 9, 30-32]

There are several possible explanations for the reductions in cortical gyrification in PD. The tension-based model of cortical morphogenesis proposes that cortical gyrification is caused mainly by the tension of the underlying white matter connectivity (both cortico-cortical and cortico-subcortical).[11, 33] Disrupted cortico-cortical and cortico-subcortical connectivity has been reported frequently in PD.[34-36] The observed volume atrophy in the hippocampus and caudate observed in the present study may also indicate possible disturbances in the cortico-subcortical connections between these two structures and the cerebral cortex.[37, 38] Therefore, the reduction in cortical gyrification may be closely related to the disrupted white matter connectivity.

Another mechanical model of brain convolutional development has also been used to explain abnormalities in cortical gyrification. This model proposes that differential growth rates of cortical layers directly affect the degree of cortical convolutions.[13] Although no direct evidence of abnormal cortical layer growth rates in PD has been provided, the gray matter volume and thickness reductions as well as the emergence of cortical Lewy bodies and Lewy neurites are suggestive of suboptimal intracortical organization,[6, 8, 21, 22] which may account for the cortical gyrification abnormalities observed in PD.

In addition, a previous study reported increased cortical gyrification in meditation practitioners,[39] indicating that established patterns of cognitive processes can affect cortical gyrification. It is tempting to speculate that the observed reductions in cortical gyrification may be related to the cognitive dysfunctions in PD.

In contrast to the extensive cortical gyrification alterations reported in neurodevelopmental disorders,[7, 17] only focal cortical gyrification alterations were observed in PD. This difference could arise because the abnormalities affecting cortical gyrification may emerge early in neurodevelopmental disorders and, thus, have more severe effects on cortical gyrification, whereas such abnormalities occur relatively late in neurodegenerative disorders such as PD (ie, after the neurodegeneration process begins) and lead to mild cortical gyrification changes.

This study had several limitations. First, most of the PD patients in our study had been prescribed dopaminergic medications; to exclude the effects of dopaminergic medications, future studies of drug-naive individuals are warranted. Second, given the heterogeneity of our sample, our data did not allow us to identify clinical correlates of the structural abnormalities in PD. To identify such correlates, further studies with more homogeneous samples are needed.

In conclusion, we identified significant reductions in cortical gyrification and subcortical atrophy in patients with PD. These morphological changes may serve as potential markers for the preclinical diagnosis and progression of PD.

Financial Disclosures

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Financial Disclosures
  7. References
  8. Supporting Information

All authors approved the article for submission. None of the authors had a conflict of interest.

References

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Financial Disclosures
  7. References
  8. Supporting Information

Supporting Information

  1. Top of page
  2. ABSTRACT
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Financial Disclosures
  7. References
  8. Supporting Information

Additional Supporting Information may be found in the online version of this article.

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