Objective: To examine the longitudinal association between tau, alpha-synuclein, and dysautonomia in Parkinson’s disease (PD).

Background: PD is characterized by dopaminergic neural loss [1] and alpha-synuclein (α-syn) aggregation [2,3]. In transgenic mice, tau protein accelerates α-syn aggregation and enhances its seeding and neurotoxicity [4]. Dysautonomia, a non-motor PD symptom [5], often leads to disabling changes in vital signs and bodily function. However, dysautonomia is also seen in tau-based forms of parkinsonism, which do not have α-syn abnormalities, suggesting this process could be based on tau and not α-syn [6]. A 2021 study using PPMI data demonstrated Scales for Outcomes in Parkinson’s Disease – Autonomic Dysfunction (SCOPA-AUT) urinary subsection scores’ correlation with CSF concentrations of phosphorylated tau (p-tau) and total tau (t-tau) in PD subjects at baseline [7]. A 2015 study showed a correlation between higher baseline α-syn-to-nerve fiber ratios with worsening of cardiovascular-related dysautonomia in PD subjects over one year [8]. However, longitudinal correlations of t-tau, p-tau, and α-syn with SCOPA-AUT score progression have yet to be established.

Method: PPMI subjects with available SCOPA-AUT scores, CSF t-tau and p-tau (n = 354) and α-syn (n = 198) at baseline and ≥ 4 one-year follow up visits for the first five years following enrollment were selected. Linear mixed effects models in R assessed relationships between biomarker concentrations and SCOPA-AUT scores over five years for each SCOPA-AUT domain, with age and sex included as covariates. One set of models evaluated p-tau and t-tau together and another evaluated α-syn. P-values were corrected with the FDR method.

Results: P-tau (p = 0.034) and t-tau (p = 0.038), were associated with cardiovascular domain SCOPA-AUT score increase over five years. A correlation was also found between p-tau (p = 0.034), t-tau (p = 0.038), and a pTau/tTau ratio (p = 0.0184) with the gastrointestinal domain. No significant association was observed between α-syn concentrations and SCOPA-AUT score progression.

Conclusion: The longitudinal association of tau protein with higher cardiovascular and gastrointestinal SCOPA-AUT score may indicate its role in the pathogenesis of dysautonomia and its utility as a potential biomarker for dysautonomia progression in PD.

Table 1. Participant Demographics

Figure 1. Forest Plots of Biomarker Effects

References: 1. Tysnes, O.-B., & Storstein, A. (2017). Epidemiology of Parkinson’s disease. Journal of Neural Transmission, 124(8), 901–905. https://doi.org/10.1007/s00702-017-1686-y
2. Burré, J., Sharma, M., & Südhof, T. C. (2017). Cell Biology and pathophysiology of α-synuclein. Cold Spring Harbor Perspectives in Medicine, 8(3). https://doi.org/10.1101/cshperspect.a024091chiar
3. Zhang, Q.-S., Heng, Y., Yuan, Y.-H., & Chen, N.-H. (2017). Pathological α-synuclein exacerbates the progression of Parkinson’s disease through microglial activation. Toxicology Letters, 265, 30–37. https://doi.org/10.1016/j.toxlet.2016.11.002
4. Pan, L., Li, C., Meng, L., Tian, Y., He, M., Yuan, X., Zhang, G., Zhang, Z., Xiong, J., Chen, G., & Zhang, Z. (2022). Tau accelerates α-synuclein aggregation and spreading in Parkinson’s disease. Brain, 145(10), 3454–3471. https://doi.org/10.1093/brain/awac171
5. Chen, Z., Li, G., & Liu, J. (2020). Autonomic dysfunction in Parkinson’s disease: Implications for pathophysiology, diagnosis, and treatment. Neurobiology of Disease, 134, 104700. https://doi.org/10.1016/j.nbd.2019.104700
6. Koga S, Aiba I. [Autonomic Dysfunction in Tauopathies]. Brain Nerve. 2022 Mar;74(3):257-262. Japanese. doi: 10.11477/mf.1416202021. PMID: 35260524.
7. Yu, Z., & Li, Y. (2021). Association of autonomic symptoms with cerebrospinal fluid biomarkers in Parkinson disease and scans without evidence of dopaminergic deficit. Medicine, 100(7), e24837. https://doi.org/10.1097/MD.0000000000024837
8. Gibbons, C. H., Wang, N., Garcia, J., Shih, L., & Freeman, R. (2015). Alpha-Synuclein and autonomic neuropathy progression in a longitudinal study of Parkinson’s disease. Autonomic Neuroscience, 192, 55. https://doi.org/10.1016/j.autneu.2015.07.440

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MDS Abstracts - https://www.mdsabstracts.org/abstract/analyzing-longitudinal-correlation-between-csf-tau-alpha-synuclein-and-dysautonomia-in-parkinsons-disease-over-five-years/