Brain Atrophy Mediates the Relationship between Misfolded Proteins Deposition and Cognitive Impairment in Parkinson’s Disease
Abstract
:1. Introduction
2. Materials and Methods
2.1. Subjects
2.2. Neurobehavioral Evaluation and Cognitive Severity Definition
2.3. Blood Sampling and Assaying of Plasma Biomarkers: T-tau, Aβ-40, Aβ-42, α-Synuclein, and Neurofilament Light Chain
2.4. Structural MRI Imaging
2.4.1. Image Acquisition
2.4.2. Image Data Processing
2.5. Statistics
2.5.1. Demographic Data
2.5.2. Partial Correlation
2.5.3. Mediation Analysis
- (a)
- The effect of plasma misfolded protein level on brain volume (indirect effect, path a);
- (b)
- The effect of brain volume on neuropsychological assessments by controlling the effect of plasma misfolded proteins (indirect effect, path b);
- (c)
- The mediation effects a × b are defined as the reduction in the relationship between the plasma misfolded proteins and the neuropsychological assessments (total relationship, path c) by including the brain volume in the model (direct path, path c).
3. Results
3.1. Basic Characteristics
3.2. Neuropsychological Assessments
3.3. Plasma Biomarkers
3.4. Brain Volume Analysis
3.5. Correlation Analysis of Plasma Misfolded Proteins, Neuropsychological Assessments, and Brain Atrophy
3.5.1. Misfolded Proteins and ROI Volumes in PD Patients
3.5.2. Neuropsychological Assessments and Brain Volumes in PD Patients
3.6. Mediation Analysis
- p-Tau–digit symbol coding relationship mediator
- Aβ42–digit symbol coding relationship mediator
- Aβ-42–abstract thinking relationship mediator
4. Discussion
4.1. Pathophysiology of Misfolded Protein Deposition and Cortical Atrophy in PD Patients
4.2. Brain Atrophy Involved in Several Neuronal Circuits in Cognitively Impaired PD Patients
4.3. Gray Matter Atrophy Contributions in Misfolded Proteins and Cognitive Impairment Correlation: Mediation Analysis
5. Limitations
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Clinical Demographics | PD 1 Patients (n = 54) | Controls (n = 37) | p |
---|---|---|---|
Age (year, mean ± SD) | 60.69 ± 8.61 | 57.65 ± 8.02 | 0.093 |
Sex (M/F) | 33/21 | 17/20 | 0.199 |
Education (year) | 11.38 ± 4.35 | 13.78 ± 3.74 | <0.001 * |
Disease duration (year) | 4.97 ± 3.32 | ||
UPDRS 2 I | 2.70 ± 2.11 | ||
UPDRS II | 11.63 ± 8.04 | ||
UPDRS III | 26.94 ± 17.53 | ||
UPDRS 176 | 41.28 ± 25.99 | ||
Modified H&Y 3 | 2.19 ± 1.22 | ||
SE-ADL 4 | 65.02 ± 28.61 | ||
MMSE 5 | 25.65 ± 3.97 | 29.16 ± 1.01 | <0.001 * |
Neuropsychological Assessments | PD 2 Patients (n = 54) | Controls (n = 37) | p |
---|---|---|---|
Attention | |||
Digit span | 10.25 ± 2.78 | 11.54 ± 1.89 | 0.174 |
Attention | 7.23 ± 0.73 | 7.73 ± 0.65 | 0.076 |
Orientation | 17.04 ± 2.36 | 17.65 ± 0.86 | 0.570 |
Executive | |||
Digit symbol coding | 7.15 ± 3.63 | 12.22 ± 2.38 | <0.001 * |
Arithmetic | 8.88 ± 2.90 | 11.08 ± 3.18 | 0.008 * |
Abstract Thinking | 8.62 ± 2.06 | 10.62 ± 1.42 | <0.001 * |
Memory | |||
Short-term memory | 9.30 ± 2.30 | 10.63 ± 2.28 | 0.163 |
Long-term memory | 9.80 ± 1.07 | 10.00 ± 0.00 | 0.876 |
Information | 9.88 ± 3.28 | 12.27 ± 3.20 | 0.012 * |
Speech and Language | |||
Comprehension | 9.71 ± 3.11 | 12.46 ± 3.05 | 0.001 * |
Language | 9.44 ± 1.06 | 9.84 ± 0.53 | 0.120 |
Semantic fluency | 7.48 ± 2.39 | 8.54 ± 1.80 | 0.025 * |
Visuospatial | |||
Picture completion | 8.40 ± 3.26 | 11.08 ± 2.98 | 0.001 * |
Block design | 7.75 ± 3.43 | 11.03 ± 2.83 | <0.001 * |
Drawing | 8.37 ± 2.51 | 9.84 ± 0.55 | 0.037 * |
CASI 1 | 84.33 ± 16.00 | 93.70 ± 4.66 | 0.028 * |
PD Brain Regions | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
Cerebellar Cortex | Caudate Nucleus | Cerebellar Cortex | Caudate Nucleus | Accumbens 1 | ||||||
Hemisphere | L 2 | L | R 3 | R | R | |||||
r | p | r | p | r | p | r | p | r | p | |
Misfolded proteins | ||||||||||
p-Tau | −0.311 | 0.005 * | −0.320 | 0.004 * | −0.342 | 0.002 * | −0.321 | 0.004 * | ||
Aβ−42 | −0.353 | 0.001 * | −0.397 | <0.001 * | −0.365 | 0.001 * | −0.422 | <0.001 * | −0.301 | 0.006 * |
Neuropsychological assessments | ||||||||||
MMSE 4 | 0.413 | <0.001 * | 0.290 | <0.001 * | 0.362 | <0.001* | 0.409 | <0.001 * | ||
Arithmetic | 0.416 | <0.001 * | 0.362 | 0.001* | ||||||
DSC 5 | 0.320 | 0.002 * | 0.318 | 0.003 * | ||||||
ABS6 | 0.291 | 0.006 * | 0.308 | 0.004 * | 0.296 | 0.005 * |
Clinical | Brain | Proteins | Path a | Path b | Path a × b | Path c′ | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Pcoef 1 | z | p | Pcoef | z | p | Pcoef | z | p | Pcoef | z | p | |||
DSC2 | RAA 4 | p-Tau | −0.318 | −0.316 | 0.002 | 0.329 | 3.245 | 0.002 | −0.193 | −1.837 | 0.070 | −0.275 | −2.664 | 0.009 |
RAA | Aβ-42 5 | −0.361 | −3.649 | <0.001 | 0.329 | 3.245 | 0.002 | −0.243 | −2.310 | 0.023 | −0.328 | −3.237 | 0.002 | |
LCC | Aβ-42 | −0.317 | −3.155 | 0.002 | 0.326 | 3.217 | 0.002 | −0.249 | −2.394 | 0.019 | −0.328 | −3.237 | 0.002 | |
ABS3 | RAA | Aβ-42 | −0.361 | −3.649 | <0.001 | 0.322 | 3.170 | 0.002 | −0.226 | −2.127 | 0.036 | −0.310 | −3.041 | 0.003 |
RCC | Aβ-42 | −0.314 | −3.125 | 0.002 | 0.314 | 3.090 | 0.003 | −0.235 | −2.243 | 0.028 | −0.310 | −3.041 | 0.003 | |
LCC | Aβ-42 | −0.317 | −3.155 | 0.002 | 0.295 | 2.878 | 0.005 | −0.240 | −2.278 | 0.025 | −0.310 | −3.041 | 0.003 |
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Yu, C.-C.; Lu, C.-Y.; Chen, M.-H.; Chen, Y.-S.; Lu, C.-H.; Lin, Y.-Y.; Chou, K.-H.; Lin, W.-C. Brain Atrophy Mediates the Relationship between Misfolded Proteins Deposition and Cognitive Impairment in Parkinson’s Disease. J. Pers. Med. 2021, 11, 702. https://doi.org/10.3390/jpm11080702
Yu C-C, Lu C-Y, Chen M-H, Chen Y-S, Lu C-H, Lin Y-Y, Chou K-H, Lin W-C. Brain Atrophy Mediates the Relationship between Misfolded Proteins Deposition and Cognitive Impairment in Parkinson’s Disease. Journal of Personalized Medicine. 2021; 11(8):702. https://doi.org/10.3390/jpm11080702
Chicago/Turabian StyleYu, Chiun-Chieh, Chia-Yin Lu, Meng-Hsiang Chen, Yueh-Sheng Chen, Cheng-Hsien Lu, Yi-Yun Lin, Kun-Hsien Chou, and Wei-Che Lin. 2021. "Brain Atrophy Mediates the Relationship between Misfolded Proteins Deposition and Cognitive Impairment in Parkinson’s Disease" Journal of Personalized Medicine 11, no. 8: 702. https://doi.org/10.3390/jpm11080702