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Plasma α-synuclein and Neurofilament Light Chain as Blood Biomarkers of Non-Motor Features in Early Parkinson’s Disease

  • 박동규 (Dong Gyu Park, 아주대학교 일반대학원)

초록/요약

Plasma α-synuclein and Neurofilament Light Chain as Blood Biomarkers of Non-Motor Features in Early Parkinson’s Disease Background and Objectives: Non-motor symptoms of Parkinson's disease （PD） are major determinants of prognosis and quality of life and often progress independently of motor severity. However, objective blood-based biomarkers reflecting non-motor disease burden and progression remain lacking. This thesis evaluated two complementary plasma biomarkers—α-synuclein and neurofilament light chain （NfL）—in early-stage PD through two independent cross-sectional studies and a longitudinal sub-study. Study 1 — Plasma α-synuclein: Total plasma α-synuclein was measured by ELISA in 37 patients with early-stage PD and 40 essential tremor （ET） controls and correlated with cardiac ¹²³I-MIBG scintigraphy and striatal ¹⁸F-FP-CIT uptake. Plasma α-synuclein did not differentiate PD from ET. Within the PD group, however, plasma α-synuclein correlated positively with the delayed cardiac MIBG heart-to-mediastinum ratio independently of age, disease duration, motor severity, and striatal dopaminergic uptake, while showing no association with striatal ¹⁸F-FP-CIT uptake. Study 2 — Plasma NfL: Plasma NfL was measured by single-molecule array （Simoa） in 70 patients with PD, 5 patients subsequently reclassified as Parkinson-plus syndromes （4 MSA and 1 DLB）, and 54 controls. Plasma NfL was significantly elevated in PD patients with orthostatic hypotension （OH） compared with both controls and PD patients without OH, and OH remained an independent correlate of plasma NfL after adjustment for age and disease duration. Plasma NfL also discriminated Parkinson-plus converters from PD （ROC AUC 0.997 versus the entire PD cohort and 0.985 versus PD with OH）. Longitudinal sub-study: In 20 PD patients from the Study 2 cohort with repeat plasma NfL measurements, paired follow-up ¹⁸F-FP-CIT PET imaging was available in 17 patients （mean inter-scan interval approximately 22 months）. Plasma NfL showed no significant longitudinal change. However, higher baseline plasma NfL was associated with a faster subsequent decline in early-phase cortical ¹⁸F-FP-CIT uptake, a surrogate marker of cortical perfusion, in the right inferior frontal gyrus. Baseline plasma NfL did not predict the rate of decline in striatal dopamine transporter uptake. Conclusions: Plasma α-synuclein and plasma NfL provide biologically distinct information regarding early PD. Plasma α-synuclein appears to reflect peripheral Lewy pathology, whereas plasma NfL reflects ongoing neuroaxonal injury and a more diffuse disease phenotype. Together, these biomarkers capture complementary dimensions of PD biology that are not adequately reflected by motor severity or nigrostriatal dopaminergic imaging and can be interpreted within the brain-first/body-first framework of PD.

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목차

I. INTRODUCTION 1
A. Parkinson’s disease 1
B. Clinical heterogeneity and the unmet biomarker need 1
C. The body-first / brain-first framework as an interpretive model 2
D. Candidate blood-based biomarkers in Parkinson’s disease 3
E. Plasma α-synuclein as a candidate biomarker 4
F. Plasma neurofilament light chain (NfL) as a candidate biomarker 6
G. Rationale, hypotheses, and aims of the thesis 7
II. MATERIALS AND METHODS 8
A. Study participants 8
1. Study 1 cohort (Plasma α-synuclein study) 8
2. Study 2 cohort (Plasma NfL study) 9
3. Longitudinal sub-cohort (NfL longitudinal sub-study) 9
B. Clinical and demographic assessments 10
1. Motor severity 10
2. Cognitive function 10
3. Assessment of probable REM sleep behavior disorder 10
4. Smell identification 11
5. Orthostatic hypotension 11
C. Neuroimaging 11
1. ¹²³I-MIBG myocardial scintigraphy 11
2. ¹⁸F-FP-CIT brain PET 12
3. Brain MRI and white matter hyperintensity grading 13
D. Plasma biomarker measurements 13
1. Sample collection and processing 13
2. Plasma α-synuclein measurement (Study 1) 13
3. Plasma NfL measurement (Study 2) 14
E. Statistical analysis 14
1. General principles 14
2. Study 1 analyses 14
3. Study 2 analyses 15
4. Longitudinal sub-study analyses 16
III. RESULTS 17
A. Plasma α-synuclein and cardiac ¹²³I-MIBG scintigraphy in early PD 17
1. Patient demographic and clinical characteristics 17
2. Comparison of plasma α-synuclein levels between PD and ET groups 18
3. Correlation between plasma α-synuclein levels and cardiac ¹²³I-MIBG uptake 19
4. Correlation with striatal dopamine transporter uptake 19
5. Multivariate analysis of plasma α-synuclein 20
6. Subgroup analyses by non-motor clinical markers 21
7. Correlation with white matter hyperintensities 21
8. Summary of Part A findings 22
B. Plasma NfL, orthostatic hypotension, and disease progression in early PD 23
1. Patient demographic and clinical characteristics 23
2. Plasma NfL levels among PD subgroups, Parkinson-plus converters, and controls 24
3. Correlations of plasma NfL with clinical and imaging features 26
4. Receiver operating characteristic analysis for Parkinson-plus conversion 27
5. Longitudinal sub-study: plasma NfL change and cortical neurodegeneration 28
6. Summary of Part B findings 35
IV. DISCUSSION 36
A. Plasma α-synuclein in early Parkinson’s disease 36
1. Lack of difference between PD and essential tremor controls 36
2. Plasma α-synuclein correlates with cardiac MIBG uptake 37
3. Plasma α-synuclein does not correlate with striatal dopaminergic loss 38
4. Subgroup analyses and white matter hyperintensities 39
B. Plasma NfL and disease progression in early Parkinson’s disease 39
1. NfL as a biomarker of neuroaxonal injury in early Parkinson's disease 40
2. Orthostatic hypotension is independently associated with elevated plasma NfL 40
3. Discrimination of Parkinson-plus converters 41
4. Longitudinal sub-study: plasma NfL and cortical perfusion decline 42
C. Implications for the brain-first/body-first model of Parkinson’s disease 42
1. The brain-first / body-first framework 42
2. Plasma α-synuclein and the body-first spectrum 43
3. Plasma NfL and the body-first spectrum 44
4. Complementarity of plasma α-synuclein and NfL 44
D. Limitations and future directions 45
V. CONCLUSION 48
VI. REFERENCES 49
국문요약 63

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