“Plasma pTau217 is associated with cognitive impairment and longitudinal cognitive decline in Parkinson’s disease”

“Plasma pTau217 is associated with cognitive impairment and longitudinal cognitive decline in Parkinson’s disease” | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article “Plasma pTau217 is associated with cognitive impairment and longitudinal cognitive decline in Parkinson’s disease” Emadoddin Kazemi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9606462/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Cognitive impairment is a major non-motor complication of Parkinson’s disease (PD), but accessible blood-based biomarkers associated with cognitive disfunction remain limited. This study investigated whether plasma phosphorylated tau at threonine 217 (pTau217) is associated with cognitive impairment and longitudinal cognitive decline in PD. Data from the Parkinson’s Progression Markers Initiative (PPMI) included 165 patients with PD with available baseline plasma pTau217 measurements. Cognitive status was classified using Montreal Cognitive Assessment (MoCA)-based criteria as normal cognition, mild cognitive impairment (MCI), or dementia-level cognitive impairment. Plasma pTau217 differed significantly across cognitive groups (P = 0.007) and was higher in patients with dementia-level cognitive impairment than in cognitively normal patients. Higher baseline plasma pTau217 was associated with lower baseline MoCA score after adjustment for age, sex, and education (β = −2.683, P = 0.009) and with greater longitudinal MoCA decline (β = −0.312, P = 0.026). Brain-derived tau (BD-tau) was not consistently associated with cognitive outcomes. In patients with MCI, baseline plasma pTau217 showed moderate discrimination for subsequent dementia conversion (area under the curve [AUC] = 0.731). These findings support plasma pTau217 as a promising blood-based marker associated with cognitive decline in PD, although validation in larger cohorts is needed. Health sciences/Biomarkers Health sciences/Diseases Health sciences/Neurology Biological sciences/Neuroscience Parkinson’s disease pTau217 plasma biomarker cognitive impairment dementia brain-derived tau Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder. Although PD is clinically defined by motor features such as bradykinesia, tremor, rigidity, and postural instability, non-motor symptoms are common from early disease stages and contribute substantially to disease burden 1 . Among these non-motor manifestations, cognitive impairment is one of the most disabling complications because it affects daily functioning, health-related quality of life, caregiver burden, and long-term prognosis 2 , 3 . Cognitive impairment in PD exists on a spectrum ranging from mild cognitive impairment (PD-MCI) to dementia. PD-MCI is common even in early disease and may progress to more severe cognitive decline over time 2 , 4 , 5 . The biological mechanisms underlying cognitive impairment in PD are heterogeneous. Although alpha-synuclein pathology is the hallmark of PD, neuropathological studies have shown that Alzheimer’s disease (AD)-related pathology, including amyloid-β and tau deposition, is frequently observed in patients with PD dementia and Lewy body disease 6 – 10 . This overlap suggests that AD-related co-pathology may contribute to cognitive decline in a subset of patients with PD. In vivo assessment of AD-related pathology has traditionally relied on cerebrospinal fluid (CSF) biomarkers or positron emission tomography (PET) imaging. However, these methods are invasive, costly, or not widely available in routine clinical settings 11 .Recent progress in blood-based biomarkers has created new opportunities for less invasive and more scalable assessment of neurodegenerative disease mechanisms 12 , 13 . Among these biomarkers, plasma phosphorylated tau at threonine 217 (pTau217) has shown strong diagnostic performance for AD-related amyloid and tau pathology and associated with cognitive decline in AD populations 14 – 16 . Emerging evidence also suggests that plasma pTau217 may detect AD-like co-pathology in Lewy body disorders, including Parkinson’s disease dementia and dementia with Lewy bodies 17 , 18 . The primary aim of this study was to determine whether baseline plasma pTau217 is associated with cognitive status as measured by the Montreal Cognitive Assessment (MoCA) and longitudinal cognitive decline in patients with PD. Plasma brain-derived tau (BD-tau) was examined as an exploratory comparator biomarker. Additionally, MCI-to-dementia conversion was examined as an exploratory analysis in patients with PD-MCI. Results Baseline characteristics of PD cognitive groups Among the 165 patients with PD included in the main analysis, 97 were classified as PD with normal cognition (PD-NC), 58 with mild cognitive impairment (PD-MCI), and 10 with dementia-level cognitive impairment (PD-D) using MoCA-based thresholds. Baseline demographic, clinical, and biomarker characteristics across cognitive groups are presented in Table 1. Age and education differed significantly across cognitive groups. Patients in the PD-D group had substantially lower education than those in the PD-NC and PD-MCI groups. Disease duration, Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) total score, Hoehn and Yahr stage, levodopa equivalent daily dose (LEDD), sex distribution, and apolipoprotein E (APOE) ε4 carrier status did not differ significantly across cognitive groups. Table 1. Demographic, clinical, and biomarker characteristics across MoCA-defined PD cognitive groups Values are median (interquartile range) unless otherwise specified. *Hoehn and Yahr stage were missing in 6 PD-NC and 3 PD-MCI participants. * MDS-UPDRS total score was missing in 9 PD-NC and 3 PD-MCI participants. *BD-tau was missing in 1 PD-NC participant. Variables PD-NC (n=97) PD-MCI (n=58) PD-D (n=10) P Value Age, years 63.30 (55.70–68.20) 67.05 (61.12–70.18) 65.40 (56.40–70.20) 0.012 Sex (Male) No, % 53.00(54.64) 33.00(56.9) 3.00(30.00) 0.282 Education, years 17.00 (14.00–18.00) 16.00 (12.00–18.00) 10.00 (7.25–13.50) 0.002 Disease duration, years 1.87 (0.89–3.70) 2.02 (0.79–4.70) 1.95 (1.12–3.51) 0.904 *MDS UPDRS-Total score 28.00 (20.00–42.25) 27.00 (21.50–39.50) 29.00 (23.25–40.25) 0.993 *Hoehn and Yahr stage 2.00 (1.00–2.00) 2.00 (1.00–2.00) 2.00 (2.00–2.00) 0.216 APOEε4 carriers, No (%) 29.00(29.90) 13.00(22.41) 3.00(30.00) 0.587 LEDD, mg/day 300.00 (0–600.00) 200.00 (100-520.90) 225.00 (118.75–415.90) 0.935 MoCA score 28.00 (27.00–29.00) 25.00 (24.00–26.00) 19.00 (18.00–20.75) 0.001 Plasma pTau217 (pg/ml) 0.0282 (0.0235–0.0407) 0.0362 (0.0228–0.0468) 0.0415 (0.0322–0.0617) 0.007 *Plasma BD Tau (pg/ml) 4.4579 (3.7255–5.5919) 5.2389 (4.2000–5.9165) 4.6150 (4.2880–6.3689) 0.045 Abbreviations : APOE, apolipoprotein E; BD-tau, brain-derived tau; LEDD, levodopa equivalent daily dose; MDS-UPDRS, Movement Disorder Society Unified Parkinson’s Disease Rating Scale; MoCA, Montreal Cognitive Assessment; PD-D, Parkinson’s disease with dementia-level cognitive impairment; PD-MCI, Parkinson’s disease with mild cognitive impairment; PD-NC, Parkinson’s disease with normal cognition; pTau217, phosphorylated tau at threonine 217. Plasma pTau217 across PD cognitive groups Plasma pTau217 concentrations had significantly different across the three MoCA-defined PD cognitive groups (Kruskal-Wallis test, n = 165, P = 0.007). Bonferroni-corrected post hoc comparisons showed that patients in the PD-D group had significantly higher plasma pTau217 concentrations than those in the PD-NC group (0.0415 [0.0322–0.0617] vs. 0.0282 [0.0235–0.0407] pg/mL; P = 0.013). Differences between PD-NC and PD-MCI and between PD-MCI and PD-D were not statistically significant after correction. Figure 1 Associations between baseline plasma pTau217 with continuous measures of baseline and longitudinal MoCA score In adjusted linear regression models, higher baseline plasma pTau217 was associated with lower baseline MoCA score among patients with PD after adjustment for age, sex, and education (n = 165; β = −2.683; 95% confidence interval [CI]: −4.694 to −0.673; P = 0.009). This indicates that higher plasma pTau217 concentrations were associated with worse global cognitive performance at baseline. ( Figure 2.A ) Longitudinal MoCA data were available for 156 patients with PD, with a mean follow-up duration of 6.74 years (standard deviation [SD] = 3.19). Higher baseline plasma pTau217 was associated with greater longitudinal decline in MoCA score after adjustment for age, sex, and education (n = 156; β = −0.312; 95% CI: −0.5875 to −0.0365; P = 0.026). ( Figure 2.B ) Secondary exploratory comparator analysis: BD-tau BD-tau was examined as an exploratory comparator biomarker. Although BD-tau showed a significant overall difference across MoCA-defined cognitive groups (Kruskal-Wallis test, n = 164, P = 0.045), post hoc comparisons were not significant after correction. In adjusted regression models, baseline BD-tau was not significantly associated with baseline MoCA score (n = 164; β = −1.60; 95% CI: −4.89 to 1.68; P = 0.337). Baseline BD-tau was also not significantly associated with longitudinal MoCA change (n = 156; β = −0.0053; 95% CI: −0.4535 to 0.443; P = 0.982). Plasma Biomarkers as Predictors of MCI to Dementia Conversion in Parkinson’s disease A subgroup of 53 patients with PD-MCI was followed longitudinally for a mean duration of 5.87 years (SD = 3.29). During follow-up, 37 patients remained clinically stable within the MCI category, whereas 16 progressed to dementia-level cognitive impairment. Baseline demographic and clinical characteristics of the MCI-stable and MCI-converter groups are presented in Table 2 . MCI-converters were older than MCI-stable participants and had shorter disease duration at baseline. Baseline MoCA score, sex distribution, education, APOE ε4 carrier status, MDS-UPDRS total score, Hoehn and Yahr stage, and LEDD did not differ significantly between groups. Table 2 . Baseline demographic and clinical characteristics of MCI-stable and MCI-converter groups Values are median (interquartile range), mean ± SD, or n (%) as appropriate. *Hoehn and Yahr stage and *MDS-UPDRS total score were missing in 3 MCI-stable participants. Variables MCI-stable (n=37) MCI-converter (n=16) P Value Average follow-up years 5.00 (3.00-9.00) 6.50 (4.75-10.00) 0.197 Age, years 64.41(8.14) 69.61(4.04) 0.027 Sex (Male) No (%) 22 (59.50) 8 (50.00) 0.736 Education, years 14.73 (4.29) 15.00 (4.05) 0.755 Disease duration, years 2.35 (1.23–4.88) 0.54 (0.34–2.43) 0.009 *MDS UPDRS Total score 30.00 (22.00–43.50) 24.50 (17.75–38.25) 0.223 *Hoehn and Yahr stage 2.00 (2.00–2.00) 2.00 (1.00–2.00) 0.075 LEDD, mg/day 300.00 (200.00-521.00) 50.00 (0-449.00) 0.056 MoCA score 25.00 (24.00–26.00) 24.50 (22.75–25.25) 0.254 APOEε4 carriers, No (%) 7 (18.90) 4 (25.00) 0.894 Plasma pTau217 (pg/ml) 0.0320 (0.0222–0.0400) 0.0483 (0.0344–0.0691) 0.008 *Plasma BD Tau (pg/ml) 5.11 (1.19) 5.76 (1.74) 0.199 Abbreviations: APOE, apolipoprotein E; BD-tau, brain-derived tau; LEDD, levodopa equivalent daily dose; MCI, mild cognitive impairment; MDS-UPDRS, Movement Disorder Society Unified Parkinson’s Disease Rating Scale; MoCA, Montreal Cognitive Assessment; pTau217, phosphorylated tau at threonine 217. Baseline plasma pTau217 was significantly higher in MCI-converters than in MCI-stable patients (Wilcoxon rank-sum test, n = 53; 0.0483 [0.0344–0.0691] vs. 0.0320 [0.0222–0.0400] pg/mL; P = 0.008). BD-tau did not differ significantly between groups (t-test, n = 53; 5.76 ± 1.74 vs. 5.11 ± 1.19; P = 0.199). Table 2, Figure 3 In a receiver operating characteristic (ROC) analysis of patients with PD-MCI, baseline plasma pTau217 showed moderate discrimination for subsequent dementia conversion (n = 53; area under the curve [AUC] = 0.7306; 95% CI: 0.5747–0.8865). A data-derived threshold of 0.0466 pg/mL was estimated for exploratory purposes, with sensitivity of 56.25% and specificity of 86.49%. This threshold should not be interpreted as a clinically validated cut-off. Figure 4 Baseline BD-tau showed lower exploratory discrimination for MCI-to-dementia conversion (n = 53; AUC = 0.6132; 95% CI: 0.4326–0.7937), with sensitivity of 56.25% and specificity of 70.27% at a data-derived threshold of 5.6635 pg/mL. Discussion In this PPMI-based observational study focused on patients with PD, higher baseline plasma pTau217 was associated with worse cognitive status, lower baseline MoCA score, and greater longitudinal decline in MoCA performance. Plasma pTau217 levels were significantly higher in patients with dementia-level cognitive impairment than in cognitively normal patients with PD. In adjusted regression models, higher baseline plasma pTau217 was associated with worse global cognitive performance at baseline and faster longitudinal cognitive decline. In an exploratory analysis of patients with PD-MCI, baseline plasma pTau217 showed moderate discrimination for subsequent dementia conversion. In contrast, BD-tau did not show consistent associations with baseline or longitudinal cognitive performance. These findings suggest that plasma pTau217 may be a useful blood-based marker of cognitive impairment in PD. The association between pTau217 and cognition is biologically plausible because pTau217 is strongly linked to AD-related tau pathology and amyloid-associated processes 14-16 . Although PD is primarily characterized by alpha-synuclein pathology, AD-related co-pathology is common in PD dementia and Lewy body disorders 6-10,17,18 Recent evidence in neuronal synuclein disease further showed that plasma pTau217 detected amyloid-β positivity with high diagnostic accuracy, supporting its potential role as a marker of mixed Alzheimer-type pathology in synucleinopathies 19 . Therefore, elevated plasma pTau217 in cognitively impaired patients with PD may reflect a subgroup with mixed pathological burden, in which tau-related mechanisms contribute to cognitive decline. The present findings are consistent with the broader literature showing that blood-based neurodegenerative biomarkers may provide clinically relevant information about cognitive outcomes in PD. Previous studies have reported associations between cognitive decline in PD and biomarkers such as neurofilament light chain and glial fibrillary acidic protein, which reflect neuronal injury and astroglial activation, respectively 20-22 The current study extends this literature by supporting plasma pTau217 as a potential marker related more specifically to AD-like tau-associated pathology in PD. The longitudinal association between baseline plasma pTau217 and subsequent MoCA decline is particularly relevant. The prognostic value of pTau217 could be a promising tool for the early detection of at-risk individuals within the disease trajectory. This is essential due to the variability of cognitive decline in Parkinson's disease, where both rates and patterns differ significantly among patients. Identifying patients who are likely to progress to dementia at an early stage could allow for targeted interventions, such as cognitive rehabilitation or emerging disease-modifying therapies, to reduce the progression of symptoms. These findings have significant clinical implications. As a plasma biomarker, pTau217 provides a non-invasive, cost-effective, and accessible alternative to cerebrospinal fluid (CSF) biomarkers and positron emission tomography (PET), which are less feasible for routine clinical use. Moreover, its prognostic accuracy indicates possible uses in clinical trials, where pTau217 could serve to classify patients according to their risk of cognitive decline, thereby enhancing trial design and outcome evaluation. BD-tau was examined as an exploratory comparator biomarker and did not show consistent associations with cognitive outcomes. This may reflect differences in biological specificity. Whereas plasma pTau217 is closely related to AD-type tau phosphorylation, BD-tau may represent broader neuronal injury or tau-related processes that are not sufficiently specific to cognitive decline in PD. Nevertheless, the interpretation of BD-tau findings remains limited, and further studies are needed to clarify its role in PD and related disorders. Our study has several limitations. First, the small sample size of our cohorts, particularly the dementia subgroup, might limit the generalizability of our results. Further studies are needed to confirm our findings. Second, while the longitudinal design is a key strength of this study, the attrition rate and the follow-up duration may have underestimated the extent and severity of cognitive decline observed over time. This limitation restricts our ability to detect potential cognitive changes linked to biomarkers, particularly BD-tau. Third, cognitive status was assessed using the MoCA, a comprehensive measure of cognition that lacks specific information on individual cognitive domains. However, we have previously shown that MoCA is a sensitive marker of cognitive change in PD. Therefore, more domain-specific associations between plasma pTau217 and BD-tau might have been undetected. Only future studies utilizing comprehensive cognitive tests will be able to explore the correlations between these biomarkers and specific cognitive aspects of PD. Finally, our study used clinical diagnosis in the absence of neuropathological confirmation. However, patients were well-characterized, and most were followed over time to obtain as accurate a clinical diagnosis as possible. In summary, although there are limitations, our findings are promising and suggest that plasma pTau217 could serve as a non-invasive and practical biomarker for predicting cognitive decline in Parkinson's disease. Further studies with larger sample sizes and longer longitudinal follow-up are needed to clarify the role of plasma pTau217 and BD-tau in PD, and to establish and validate biomarkers thresholds that could be used in clinical practice. Conclusions In conclusion, we demonstrate that plasma pTau217 levels are elevated in PD patients with cognitive impairment, but not in those with normal cognition. We also suggest that plasma pTau217 may have potential prognostic relevance for identifying patients with PD-MCI at increased risk of dementia-level cognitive decline. Materials and Methods Study design and data source Data were downloaded from the PPMI database (http://www.ppmi-info.org). The PPMI is an ongoing, observational, longitudinal, prospective, international multicenter study that intends to identify biomarkers for the progression of PD. The analysis was designed to evaluate whether baseline plasma pTau217 is associated with cognitive status and longitudinal cognitive decline among patients with PD. Plasma BD-tau was evaluated as an exploratory comparator biomarker. The MCI-to-dementia conversion analysis was considered exploratory analysis. Participants A total of 198 participants were initially included in the study, all of whom had available plasma phosphorylated tau 217 (pTau217) concentrations at baseline. This cohort comprised 165 individuals diagnosed with Parkinson’s disease (PD), 25 healthy controls (HCs), and 8 prodromal subjects. To simplify the analysis and interpretation of results, the 8 prodromal subjects were excluded. Because the objective of this study was to evaluate cognition-related biomarker associations within PD, the primary analysis focused on the 165 patients with PD. Healthy controls were not included in the primary analyses; descriptive comparisons between healthy controls and patients with PD are provided as Supplementary Table S1. Participants with de novo PD were eligible for PPMI if they were aged 30 years or older at diagnosis, had disease duration of 2 years or less at enrollment, had at least two cardinal motor features or isolated asymmetric bradykinesia or tremor, had no dementia at enrollment based on clinical assessment, had not received prior PD treatment, and had no use of medications that could interfere with dopamine transporter imaging or cerebrospinal fluid collection. To reduce the risk of misdiagnosis, longitudinal clinical follow-up was conducted, and individuals later diagnosed with atypical Parkinsonian syndromes such as progressive supranuclear palsy (PSP) or multiple system atrophy (MSA) were excluded. Healthy controls were required to have no clinically significant neurological impairments, no first-degree relatives with Parkinson's disease (PD), and a baseline Montreal Cognitive Assessment (MoCA) score of 26 or higher. In line with the study objectives, MoCA scores were extracted at baseline and at periodic follow-up time points for both cross-sectional and longitudinal analyses of cognitive performance. Data for our analysis were limited to participants with no missing baseline MoCA score and at least one additional MoCA score for follow-up assessments. These data were used to explore the relationship between baseline plasma pTau217 levels and cognitive trajectories over time. Clinical assessment measures Disease severity was evaluated using the MDS-UPDRS-Total score and the H&Y scale (which includes ON and untreated scores) 23 . The dosage of antiparkinsonian drugs was converted into a Total Levodopa Equivalent Daily Dose (LEDD) 24 . The MoCA was performed to assess global cognitive function. It is the most commonly used cognitive measurement in PD and has an elevated specificity and sensitivity for distinguishing MCI in PD 25 . The MoCA was used to assess global cognitive function because it is brief, widely used in Parkinson’s disease studies, and suitable for large multicenter cohorts. It evaluates several cognitive domains commonly affected in PD, has been validated in multiple languages, and requires substantially less time and training to administer than a comprehensive neuropsychological assessment 26 . In the present study, cognitive status was defined based on the criteria of the MDS level I guideline: PD with normal cognition (PD-NC) if the MoCA score was >26, PD-MCI if the score was between 22 and 26, and PD-D if the score was <22 27,28 Because these categories were based on MoCA thresholds rather than comprehensive neuropsychological testing or formal adjudicated dementia diagnosis, the PD-D group was interpreted as representing dementia-level global cognitive impairment rather than clinically confirmed Parkinson’s disease dementia Plasma biomarker measurements A subset of the PPMI cohort, consisting of 198 subjects, was selected to evaluate Alzheimer’s disease-related Tau biomarkers. For each participant, two 200-µL K2EDTA plasma aliquots were sent to Quanterix, Billerica, MA, USA, for duplicate measurement of plasma pTau217 and BD-tau. Plasma pTau217 was measured using the LucentAD p217 test, a laboratory-developed test based on the research-use-only Janssen plasma p217+Tau assay 29,30 . Additional analytical and clinical validation details for the LucentAD p217 assay have been described previously 31 . BD-tau was measured using a Janssen-designed assay using Janssen mAb hT43 as the capture antibody and Janssen mAb pT82 as the detector antibody. Genotyping Genomic DNA was extracted from whole blood samples from PD participants. Apolipoprotein E (APOE) genotyping was performed using allele-specific oligonucleotide probes labeled with a fluorogenic reporter using the TaqMan method 32 . Participants were classified as APOE ε4 carriers or non-carriers according to the presence or absence of at least one ε4 allele. Statistical Analysis For statistical analysis, the programming language R, version 4.4.1, was utilized. The normality distribution assumption was tested with Shapiro-Wilk tests. Normally distributed continuous variables were summarized as mean ± SD, whereas non-normally distributed variables were summarized as median and interquartile range. Categorical variables were summarized as number and percentage. We used the Kruskal-Wallis test or one-way ANOVA to compare continuous variables across the PD subgroups, and Pearson’s chi-square test was used to compare categorical variables. We also compared plasma biomarker levels (pTau217 and BD-tau) using the Kruskal-Wallis test between PD subgroups, followed by a Bonferroni-corrected post hoc test to reduce the risk of inflated type I error due to multiple pairwise comparisons. Associations between plasma biomarkers and MoCA scores at baseline were examined using linear regression models that adjusted for age, sex, and education. For associations with longitudinal MoCA scores, we first derived individual slopes of MoCA scores in the PPMI study using linear mixed-effects models, which included longitudinal MoCA scores as the outcome and time (in years since baseline) as predictors, with random slopes and intercepts. Similarly, associations between baseline levels of pTau217 and BD-tau with MoCA slopes were tested using linear regression models adjusting for age, sex, and education. In the regression analysis, plasma biomarker measures were log10-transformed to better fit the normal distribution. For the exploratory MCI-to-dementia conversion analysis, patients with baseline PD-MCI were classified as MCI-stable or MCI-converter according to whether they progressed to MoCA-defined dementia-level cognitive impairment during follow-up. Between-group comparisons were performed using the t-test or Wilcoxon rank-sum test based on normality distribution and Pearson’s chi-square test for categorical variables. The discriminative accuracies of plasma biomarkers between groups were assessed using receiver operating characteristic (ROC) curve analysis. The area under the curve (AUC), 95% confidence interval, sensitivity, and specificity were reported. Data-derived thresholds were estimated by maximizing Youden’s index All statistical tests were two-sided, and P <0.05 was considered statistically significant. Exact P values are reported wherever possible. Analyses were performed using available cases for each model, and missing values are reported in table footnotes Declarations Ethics approval and consent to participate : The PPMI study was approved by the institutional review boards or ethics committees at all participating sites. All participants provided written informed consent before enrollment. The present analysis used de-identified data obtained from the PPMI database. All methods were performed in accordance with the relevant guidelines and regulations. Consent for publication : Not applicable Competing interests : The authors disclose no financial, personal, or institutional conflicts of interest related to this article. Funding : This study was carried out without any funding or financial support. Authors' contributions: EK conceptualized and designed the study, collected and curated the data, performed the statistical analyses, prepared the figures, drafted the initial manuscript, and revised the manuscript. Use of artificial intelligence-assisted tools During manuscript preparation, the author used ChatGPT to assist with language editing, structural refinement, and readability improvement. The author reviewed and edited all AI-assisted text and takes full responsibility for the content, accuracy, interpretation, and integrity of the manuscript. Acknowledgements : Parkinson’s Progression Markers Initiative (a public–private partnership) is funded by the Michael J Fox Foundation for Parkinson’s Research and funding partners, including AbbVie, Allergan, Avid Radiopharmaceuticals, Biogen, BioLegend, Bristol-Myers Squibb, Celgene, Denali, GE Healthcare, Genentech, GlaxoSmithKline, Lilly, Lundbeck, Merck, Meso Scale Discovery, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, Verily, Voyager Therapeutics, and Golub Capital. Data used in the preparation of this article were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). For up-to-date information on the study, visit www.ppmi-info. Availability of data and materials The datasets used and/or analyzed during the current study are available from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). References Schapira, A. H., Chaudhuri, K. R. & Jenner, P. 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Systematic review of levodopa dose equivalency reporting in Parkinson's disease. Mov. Disord. 25 , 2649–2653 (2010). Hendershott, T. R., Zhu, D., Llanes, S. & Poston, K. L. Domain-specific accuracy of the Montreal Cognitive Assessment subsections in Parkinson's disease. Parkinsonism Relat. Disord. 38 , 31–34 (2017). Chou, K. L. et al. Vol. 25 2501–2507 (2010). Wiley Online Library. Chahine, L. et al. Longitudinal changes in cognition in early Parkinson's disease patients with REM sleep behavior disorder. Parkinsonism Relat. Disord. 27 , 102–106 (2016). Litvan, I. et al. Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines. Mov. Disord. 27 , 349–356 (2012). Triana-Baltzer, G. et al. Development and validation of a high-sensitivity assay for measuring p217 + tau in plasma. Alzheimers Dement. (Amst) . 13 , e12204. 10.1002/dad2.12204 (2021). Doré, V. et al. Plasma p217 + tau versus NAV4694 amyloid and MK6240 tau PET across the Alzheimer's continuum. Alzheimers Dement. (Amst) . 14 , e12307. 10.1002/dad2.12307 (2022). Wilson, D. et al. Analytical and Clinical Validation of a High Accuracy Fully Automated Digital Immunoassay for Plasma Phospho-Tau 217 for Clinical Use in Detecting Amyloid Pathology. medRxiv , 2024.2010.2031.24316186, (2024). 10.1101/2024.10.31.24316186 Kang, J. H. et al. CSF biomarkers associated with disease heterogeneity in early Parkinson’s disease: the Parkinson’s Progression Markers Initiative study. Acta Neuropathol. 131 , 935–949 (2016). Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterial208.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9606462","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":638391645,"identity":"025e3a11-7ae8-4898-9471-23bf3d895e18","order_by":0,"name":"Emadoddin Kazemi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYJACyQYQycx88MEHIM3GTrwWtmTDGSAtzERrYeAxk+YB6yWgnF/s8MObM2rq5HTbgVpsfm2T52NmYPzwMQePDbPTjC03HGMzNjvMVmyd23fbsI2ZgVly5jbcWgxuJ5hJPmDjSdx2mHnj7dye24xALWzMvHi02N9O/yb54J9E/bbDDAbSlj237QlqMZDOMZPc2GaQYHaYxUia4cftRIJaJG7nFFvO7Esw3HYYGMi9DbeT25gZm/H6hX92+sabPd/q5M3OHz744Mef27bz25sPfviIRwsqYGwDkw3EqgeBP6QoHgWjYBSMgpECAPvSUGpRGhqUAAAAAElFTkSuQmCC","orcid":"","institution":"Arak University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Emadoddin","middleName":"","lastName":"Kazemi","suffix":""}],"badges":[],"createdAt":"2026-05-04 09:23:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9606462/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9606462/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109102267,"identity":"a627f855-1e92-4647-b3f1-e24764ca358c","added_by":"auto","created_at":"2026-05-12 14:31:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":120325,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of Plasma pTau217 levels in PD subgroups (NC, MCI, and Dementia)\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9606462/v1/2219740a78c1857b769fa836.png"},{"id":109102344,"identity":"22269401-f09e-4758-961e-df5208cc35d5","added_by":"auto","created_at":"2026-05-12 14:31:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":227033,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA.\u003c/strong\u003e Associations between baseline pTau217 levels and baseline MoCA score\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB. \u003c/strong\u003e\u0026nbsp;Associations between baseline pTau217 levels and participant-specific slopes of MoCA score\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9606462/v1/4eb4750c99fc5c341e2559c5.png"},{"id":109204791,"identity":"8c77bffb-d8a0-4d43-aaa0-0b3816403a27","added_by":"auto","created_at":"2026-05-13 15:02:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":103641,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of Plasma pTau217 levels in converter and non-converter PD patients\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9606462/v1/5f0ba1c73c493bc4852f5f20.png"},{"id":109102269,"identity":"ebc3bf9c-fc1a-484a-bdde-c04a3bfa05c4","added_by":"auto","created_at":"2026-05-12 14:31:48","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":81955,"visible":true,"origin":"","legend":"\u003cp\u003eThe ROC curve for Plasma pTau217 levels in converter and non-converter PD patients\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-9606462/v1/149b861b76019b69a016963a.png"},{"id":109206671,"identity":"324c7479-6fde-4a5a-b94c-012fc5a55ca5","added_by":"auto","created_at":"2026-05-13 15:15:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":762764,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9606462/v1/8e171975-f8a6-4a99-bf74-9ebc47bca85f.pdf"},{"id":109102323,"identity":"7988e1e2-c636-4954-a6ad-9206fd2524a5","added_by":"auto","created_at":"2026-05-12 14:31:55","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":18126,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial208.docx","url":"https://assets-eu.researchsquare.com/files/rs-9606462/v1/33194283897910200ecb641f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"“Plasma pTau217 is associated with cognitive impairment and longitudinal cognitive decline in Parkinson’s disease”","fulltext":[{"header":"Introduction","content":"\u003cp\u003eParkinson\u0026rsquo;s disease (PD) is the second most common progressive neurodegenerative disorder. Although PD is clinically defined by motor features such as bradykinesia, tremor, rigidity, and postural instability, non-motor symptoms are common from early disease stages and contribute substantially to disease burden \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Among these non-motor manifestations, cognitive impairment is one of the most disabling complications because it affects daily functioning, health-related quality of life, caregiver burden, and long-term prognosis \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Cognitive impairment in PD exists on a spectrum ranging from mild cognitive impairment (PD-MCI) to dementia. PD-MCI is common even in early disease and may progress to more severe cognitive decline over time \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe biological mechanisms underlying cognitive impairment in PD are heterogeneous. Although alpha-synuclein pathology is the hallmark of PD, neuropathological studies have shown that Alzheimer\u0026rsquo;s disease (AD)-related pathology, including amyloid-β and tau deposition, is frequently observed in patients with PD dementia and Lewy body disease\u003csup\u003e\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. This overlap suggests that AD-related co-pathology may contribute to cognitive decline in a subset of patients with PD.\u003c/p\u003e \u003cp\u003eIn vivo assessment of AD-related pathology has traditionally relied on cerebrospinal fluid (CSF) biomarkers or positron emission tomography (PET) imaging. However, these methods are invasive, costly, or not widely available in routine clinical settings \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.Recent progress in blood-based biomarkers has created new opportunities for less invasive and more scalable assessment of neurodegenerative disease mechanisms \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAmong these biomarkers, plasma phosphorylated tau at threonine 217 (pTau217) has shown strong diagnostic performance for AD-related amyloid and tau pathology and associated with cognitive decline in AD populations\u003csup\u003e\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Emerging evidence also suggests that plasma pTau217 may detect AD-like co-pathology in Lewy body disorders, including Parkinson\u0026rsquo;s disease dementia and dementia with Lewy bodies \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe primary aim of this study was to determine whether baseline plasma pTau217 is associated with cognitive status as measured by the Montreal Cognitive Assessment (MoCA) and longitudinal cognitive decline in patients with PD. Plasma brain-derived tau (BD-tau) was examined as an exploratory comparator biomarker. Additionally, MCI-to-dementia conversion was examined as an exploratory analysis in patients with PD-MCI.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBaseline characteristics of PD cognitive groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 165 patients with PD included in the main analysis, 97 were classified as PD with normal cognition (PD-NC), 58 with mild cognitive impairment (PD-MCI), and 10 with dementia-level cognitive impairment (PD-D) using MoCA-based thresholds. Baseline demographic, clinical, and biomarker characteristics across cognitive groups are presented in \u003cstrong\u003eTable 1.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAge and education differed significantly across cognitive groups. Patients in the PD-D group had substantially lower education than those in the PD-NC and PD-MCI groups. Disease duration, Movement Disorder Society Unified Parkinson\u0026rsquo;s Disease Rating Scale (MDS-UPDRS) total score, Hoehn and Yahr stage, levodopa equivalent daily dose (LEDD), sex distribution, and apolipoprotein E (APOE) \u0026epsilon;4 carrier status did not differ significantly across cognitive groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Demographic, clinical, and biomarker characteristics across MoCA-defined PD cognitive groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eValues are median (interquartile range) unless otherwise specified. *Hoehn and Yahr stage were missing in 6 PD-NC and 3 PD-MCI participants. * MDS-UPDRS total score was missing in 9 PD-NC and 3 PD-MCI participants. *BD-tau was missing in 1 PD-NC participant.\u003c/p\u003e\n\u003ctable\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePD-NC (n=97)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePD-MCI (n=58)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePD-D (n=10)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eP\u0026nbsp;Value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e63.30 (55.70\u0026ndash;68.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e67.05 (61.12\u0026ndash;70.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e65.40 (56.40\u0026ndash;70.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSex (Male) No, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e53.00(54.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33.00(56.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.00(30.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.282\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eEducation, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17.00 (14.00\u0026ndash;18.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16.00 (12.00\u0026ndash;18.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10.00 (7.25\u0026ndash;13.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDisease duration, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.87 (0.89\u0026ndash;3.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.02 (0.79\u0026ndash;4.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.95 (1.12\u0026ndash;3.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.904\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e*MDS UPDRS-Total score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28.00 (20.00\u0026ndash;42.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27.00 (21.50\u0026ndash;39.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29.00 (23.25\u0026ndash;40.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.993\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e*Hoehn and Yahr stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.00 (1.00\u0026ndash;2.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.00 (1.00\u0026ndash;2.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.00 (2.00\u0026ndash;2.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.216\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAPOE\u0026epsilon;4 carriers, No (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29.00(29.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13.00(22.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.00(30.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.587\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eLEDD, mg/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e300.00 (0\u0026ndash;600.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e200.00 (100-520.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e225.00 (118.75\u0026ndash;415.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.935\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMoCA score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28.00 (27.00\u0026ndash;29.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e25.00 (24.00\u0026ndash;26.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19.00 (18.00\u0026ndash;20.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePlasma pTau217 (pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0282 (0.0235\u0026ndash;0.0407)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0362 (0.0228\u0026ndash;0.0468)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0415 (0.0322\u0026ndash;0.0617)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e*Plasma BD Tau (pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.4579 (3.7255\u0026ndash;5.5919)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5.2389 (4.2000\u0026ndash;5.9165)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.6150 (4.2880\u0026ndash;6.3689)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.045\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003cstrong\u003eAbbreviations\u003c/strong\u003e: APOE, apolipoprotein E; BD-tau, brain-derived tau; LEDD, levodopa equivalent daily dose; MDS-UPDRS, Movement Disorder Society Unified Parkinson\u0026rsquo;s Disease Rating Scale; MoCA, Montreal Cognitive Assessment; PD-D, Parkinson\u0026rsquo;s disease with dementia-level cognitive impairment; PD-MCI, Parkinson\u0026rsquo;s disease with mild cognitive impairment; PD-NC, Parkinson\u0026rsquo;s disease with normal cognition; pTau217, phosphorylated tau at threonine 217.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlasma pTau217 across PD cognitive groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePlasma pTau217 concentrations had significantly different across the three MoCA-defined PD cognitive groups (Kruskal-Wallis test, n = 165, P = 0.007). Bonferroni-corrected post hoc comparisons showed that patients in the PD-D group had significantly higher plasma pTau217 concentrations than those in the PD-NC group (0.0415 [0.0322\u0026ndash;0.0617] vs. 0.0282 [0.0235\u0026ndash;0.0407] pg/mL; P = 0.013). Differences between PD-NC and PD-MCI and between PD-MCI and PD-D were not statistically significant after correction. \u003cstrong\u003eFigure 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssociations between baseline plasma pTau217 with continuous measures of baseline and longitudinal MoCA score\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn adjusted linear regression models, higher baseline plasma pTau217 was associated with lower baseline MoCA score among patients with PD after adjustment for age, sex, and education (n = 165; \u0026beta; = \u0026minus;2.683; 95% confidence interval [CI]: \u0026minus;4.694 to \u0026minus;0.673; P = 0.009). This indicates that higher plasma pTau217 concentrations were associated with worse global cognitive performance at baseline. (\u003cstrong\u003eFigure 2.A\u003c/strong\u003e)\u003c/p\u003e\n\u003cp\u003eLongitudinal MoCA data were available for 156 patients with PD, with a mean follow-up duration of 6.74 years (standard deviation [SD] = 3.19). Higher baseline plasma pTau217 was associated with greater longitudinal decline in MoCA score after adjustment for age, sex, and education (n = 156; \u0026beta; = \u0026minus;0.312; 95% CI: \u0026minus;0.5875 to \u0026minus;0.0365; P = 0.026). (\u003cstrong\u003eFigure 2.B\u003c/strong\u003e)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary exploratory comparator analysis: BD-tau\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBD-tau was examined as an exploratory comparator biomarker. Although BD-tau showed a significant overall difference across MoCA-defined cognitive groups (Kruskal-Wallis test, n = 164, P = 0.045), post hoc comparisons were not significant after correction. In adjusted regression models, baseline BD-tau was not significantly associated with baseline MoCA score (n = 164; \u0026beta; = \u0026minus;1.60; 95% CI: \u0026minus;4.89 to 1.68; P = 0.337). Baseline BD-tau was also not significantly associated with longitudinal MoCA change (n = 156; \u0026beta; = \u0026minus;0.0053; 95% CI: \u0026minus;0.4535 to 0.443; P = 0.982).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlasma Biomarkers as Predictors of MCI to Dementia Conversion in Parkinson\u0026rsquo;s disease\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA subgroup of 53 patients with PD-MCI was followed longitudinally for a mean duration of 5.87 years (SD = 3.29). During follow-up, 37 patients remained clinically stable within the MCI category, whereas 16 progressed to dementia-level cognitive impairment.\u003c/p\u003e\n\u003cp\u003eBaseline demographic and clinical characteristics of the MCI-stable and MCI-converter groups are presented in \u003cstrong\u003eTable 2\u003c/strong\u003e. MCI-converters were older than MCI-stable participants and had shorter disease duration at baseline. Baseline MoCA score, sex distribution, education, APOE \u0026epsilon;4 carrier status, MDS-UPDRS total score, Hoehn and Yahr stage, and LEDD did not differ significantly between groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e. \u003cstrong\u003eBaseline demographic and clinical characteristics of MCI-stable and MCI-converter groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eValues are median (interquartile range), mean \u0026plusmn; SD, or n (%) as appropriate. *Hoehn and Yahr stage and *MDS-UPDRS total score were missing in 3 MCI-stable participants.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMCI-stable (n=37)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMCI-converter\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=16)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eP\u0026nbsp;Value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAverage follow-up years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5.00 (3.00-9.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6.50 (4.75-10.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.197\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e64.41(8.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e69.61(4.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.027\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSex (Male) No (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22 (59.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 (50.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.736\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eEducation, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14.73 (4.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15.00 (4.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.755\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDisease duration, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.35 (1.23\u0026ndash;4.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.54 (0.34\u0026ndash;2.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e*MDS UPDRS Total score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30.00 (22.00\u0026ndash;43.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24.50 (17.75\u0026ndash;38.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.223\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e*Hoehn and Yahr stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.00 (2.00\u0026ndash;2.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.00 (1.00\u0026ndash;2.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.075\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eLEDD, mg/day\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e300.00 (200.00-521.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e50.00 (0-449.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.056\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMoCA score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e25.00 (24.00\u0026ndash;26.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24.50 (22.75\u0026ndash;25.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.254\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAPOE\u0026epsilon;4 carriers, No (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7 (18.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4 (25.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.894\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePlasma pTau217 (pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0320 (0.0222\u0026ndash;0.0400)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.0483 (0.0344\u0026ndash;0.0691)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e*Plasma BD Tau (pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5.11 (1.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5.76 (1.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.199\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e APOE, apolipoprotein E; BD-tau, brain-derived tau; LEDD, levodopa equivalent daily dose; MCI, mild cognitive impairment; MDS-UPDRS, Movement Disorder Society Unified Parkinson\u0026rsquo;s Disease Rating Scale; MoCA, Montreal Cognitive Assessment; pTau217, phosphorylated tau at threonine 217.\u003c/p\u003e\n\u003cp\u003eBaseline plasma pTau217 was significantly higher in MCI-converters than in MCI-stable patients (Wilcoxon rank-sum test, n = 53; 0.0483 [0.0344\u0026ndash;0.0691] vs. 0.0320 [0.0222\u0026ndash;0.0400] pg/mL; P = 0.008). BD-tau did not differ significantly between groups (t-test, n = 53; 5.76 \u0026plusmn; 1.74 vs. 5.11 \u0026plusmn; 1.19; P = 0.199). \u003cstrong\u003eTable 2, Figure 3\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn a receiver operating characteristic (ROC) analysis of patients with PD-MCI, baseline plasma pTau217 showed moderate discrimination for subsequent dementia conversion (n = 53; area under the curve [AUC] = 0.7306; 95% CI: 0.5747\u0026ndash;0.8865). A data-derived threshold of 0.0466 pg/mL was estimated for exploratory purposes, with sensitivity of 56.25% and specificity of 86.49%. This threshold should not be interpreted as a clinically validated cut-off. \u003cstrong\u003eFigure 4\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBaseline BD-tau showed lower exploratory discrimination for MCI-to-dementia conversion (n = 53; AUC = 0.6132; 95% CI: 0.4326\u0026ndash;0.7937), with sensitivity of 56.25% and specificity of 70.27% at a data-derived threshold of 5.6635 pg/mL.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this PPMI-based observational study focused on patients with PD, higher baseline plasma pTau217 was associated with worse cognitive status, lower baseline MoCA score, and greater longitudinal decline in MoCA performance. Plasma pTau217 levels were significantly higher in patients with dementia-level cognitive impairment than in cognitively normal patients with PD. In adjusted regression models, higher baseline plasma pTau217 was associated with worse global cognitive performance at baseline and faster longitudinal cognitive decline. In an exploratory analysis of patients with PD-MCI, baseline plasma pTau217 showed moderate discrimination for subsequent dementia conversion. In contrast, BD-tau did not show consistent associations with baseline or longitudinal cognitive performance.\u003c/p\u003e\n\u003cp\u003eThese findings suggest that plasma pTau217 may be a useful blood-based marker of cognitive impairment in PD. The association between pTau217 and cognition is biologically plausible because pTau217 is strongly linked to AD-related tau pathology and amyloid-associated processes \u003csup\u003e14-16\u003c/sup\u003e. Although PD is primarily characterized by alpha-synuclein pathology, AD-related co-pathology is common in PD dementia and Lewy body disorders \u003csup\u003e6-10,17,18\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRecent evidence in neuronal synuclein disease further showed that plasma pTau217 detected amyloid-β positivity with high diagnostic accuracy, supporting its potential role as a marker of mixed Alzheimer-type pathology in synucleinopathies\u003csup\u003e19\u003c/sup\u003e. Therefore, elevated plasma pTau217 in cognitively impaired patients with PD may reflect a subgroup with mixed pathological burden, in which tau-related mechanisms contribute to cognitive decline.\u003c/p\u003e\n\u003cp\u003eThe present findings are consistent with the broader literature showing that blood-based neurodegenerative biomarkers may provide clinically relevant information about cognitive outcomes in PD. Previous studies have reported associations between cognitive decline in PD and biomarkers such as neurofilament light chain and glial fibrillary acidic protein, which reflect neuronal injury and astroglial activation, respectively \u003csup\u003e20-22\u003c/sup\u003e The current study extends this literature by supporting plasma pTau217 as a potential marker related more specifically to AD-like tau-associated pathology in PD.\u003c/p\u003e\n\u003cp\u003eThe longitudinal association between baseline plasma pTau217 and subsequent MoCA decline is particularly relevant. The prognostic value of pTau217 could be a promising tool for the early detection of at-risk individuals within the disease trajectory. This is essential due to the variability of cognitive decline in Parkinson's disease, where both rates and patterns differ significantly among patients.\u003c/p\u003e\n\u003cp\u003eIdentifying patients who are likely to progress to dementia at an early stage could allow for targeted interventions, such as cognitive rehabilitation or emerging disease-modifying therapies, to reduce the progression of symptoms. These findings have significant clinical implications. As a plasma biomarker, pTau217 provides a non-invasive, cost-effective, and accessible alternative to cerebrospinal fluid (CSF) biomarkers and positron emission tomography (PET), which are less feasible for routine clinical use. Moreover, its prognostic accuracy indicates possible uses in clinical trials, where pTau217 could serve to classify patients according to their risk of cognitive decline, thereby enhancing trial design and outcome evaluation.\u003c/p\u003e\n\u003cp\u003eBD-tau was examined as an exploratory comparator biomarker and did not show consistent associations with cognitive outcomes. This may reflect differences in biological specificity. Whereas plasma pTau217 is closely related to AD-type tau phosphorylation, BD-tau may represent broader neuronal injury or tau-related processes that are not sufficiently specific to cognitive decline in PD. Nevertheless, the interpretation of BD-tau findings remains limited, and further studies are needed to clarify its role in PD and related disorders.\u003c/p\u003e\n\u003cp\u003eOur study has several limitations. First, the small sample size of our cohorts, particularly the dementia subgroup, might limit the generalizability of our results. Further studies are needed to confirm our findings. Second, while the longitudinal design is a key strength of this study, the attrition rate and the follow-up duration may have underestimated the extent and severity of cognitive decline observed over time. This limitation restricts our ability to detect potential cognitive changes linked to biomarkers, particularly BD-tau.\u0026nbsp;Third, cognitive status was assessed using the MoCA, a comprehensive measure of cognition that lacks specific information on individual cognitive domains. However, we have previously shown that MoCA is a sensitive marker of cognitive change in PD.\u003c/p\u003e\n\u003cp\u003eTherefore, more domain-specific associations between plasma pTau217 and BD-tau might have been undetected. Only future studies utilizing comprehensive cognitive tests will be able to explore the correlations between these biomarkers and specific cognitive aspects of PD. Finally, our study used clinical diagnosis in the absence of neuropathological confirmation. However, patients were well-characterized, and most were followed over time to obtain as accurate a clinical diagnosis as possible.\u003c/p\u003e\n\u003cp\u003eIn summary, although there are limitations, our findings are promising and suggest that plasma pTau217 could serve as a non-invasive and practical biomarker for predicting cognitive decline in Parkinson's disease.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFurther studies with larger sample sizes and longer longitudinal follow-up are needed to clarify the role of plasma pTau217 and BD-tau in PD, and to establish and validate biomarkers thresholds that could be used in clinical practice.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, we demonstrate that plasma pTau217 levels are elevated in PD patients with cognitive impairment, but not in those with normal cognition. We also suggest that plasma pTau217 may have potential prognostic relevance for identifying patients with PD-MCI at increased risk of dementia-level cognitive decline.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design and data source\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData were downloaded from the PPMI database (http://www.ppmi-info.org). The PPMI is an ongoing, observational, longitudinal, prospective, international multicenter study that intends to identify biomarkers for the progression of PD.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe analysis was designed to evaluate whether baseline plasma pTau217 is associated with cognitive status and longitudinal cognitive decline among patients with PD. Plasma BD-tau was evaluated as an exploratory comparator biomarker. The MCI-to-dementia conversion analysis was considered exploratory analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipants\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 198 participants were initially included in the study, all of whom had available plasma phosphorylated tau 217 (pTau217) concentrations at baseline. This cohort comprised 165 individuals diagnosed with Parkinson\u0026rsquo;s disease (PD), 25 healthy controls (HCs), and 8 prodromal subjects. To simplify the analysis and interpretation of results, the 8 prodromal subjects were excluded. Because the objective of this study was to evaluate cognition-related biomarker associations within PD, the primary analysis focused on the 165 patients with PD. Healthy controls were not included in the primary analyses; descriptive comparisons between healthy controls and patients with PD are provided as \u003cstrong\u003eSupplementary Table S1.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants with de novo PD were eligible for PPMI if they were aged 30 years or older at diagnosis, had disease duration of 2 years or less at enrollment, had at least two cardinal motor features or isolated asymmetric bradykinesia or tremor, had no dementia at enrollment based on clinical assessment, had not received prior PD treatment, and had no use of medications that could interfere with dopamine transporter imaging or cerebrospinal fluid collection. To reduce the risk of misdiagnosis, longitudinal clinical follow-up was conducted, and individuals later diagnosed with atypical Parkinsonian syndromes such as progressive supranuclear palsy (PSP) or multiple system atrophy (MSA) were excluded.\u003c/p\u003e\n\u003cp\u003eHealthy controls were required to have no clinically significant neurological impairments, no first-degree relatives with Parkinson\u0026apos;s disease (PD), and a baseline Montreal Cognitive Assessment (MoCA) score of 26 or higher.\u003c/p\u003e\n\u003cp\u003eIn line with the study objectives, MoCA scores were extracted at baseline and at periodic follow-up time points for both cross-sectional and longitudinal analyses of cognitive performance.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData for our analysis were limited to participants with no missing baseline MoCA score and at least one additional MoCA score for follow-up assessments. These data were used to explore the relationship between baseline plasma pTau217 levels and cognitive trajectories over time.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical assessment measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDisease severity was evaluated using the MDS-UPDRS-Total score and the H\u0026amp;Y scale (which includes ON and untreated scores) \u003csup\u003e23\u003c/sup\u003e. The dosage of antiparkinsonian drugs was converted into a Total Levodopa Equivalent Daily Dose (LEDD) \u003csup\u003e24\u003c/sup\u003e. The MoCA was performed to assess global cognitive function. It is the most commonly used cognitive measurement in PD and has an elevated specificity and sensitivity for distinguishing MCI in PD \u003csup\u003e25\u003c/sup\u003e. The MoCA was used to assess global cognitive function because it is brief, widely used in Parkinson\u0026rsquo;s disease studies, and suitable for large multicenter cohorts. It evaluates several cognitive domains commonly affected in PD, has been validated in multiple languages, and requires substantially less time and training to administer than a comprehensive neuropsychological assessment\u003csup\u003e26\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the present study, cognitive status was defined based on the criteria of the MDS level I guideline: PD with normal cognition (PD-NC) if the MoCA score was \u0026gt;26, PD-MCI if the score was between 22 and 26, and PD-D if the score was \u0026lt;22 \u003csup\u003e27,28\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eBecause these categories were based on MoCA thresholds rather than comprehensive neuropsychological testing or formal adjudicated dementia diagnosis, the PD-D group was interpreted as representing dementia-level global cognitive impairment rather than clinically confirmed Parkinson\u0026rsquo;s disease dementia\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlasma biomarker measurements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA subset of the PPMI cohort, consisting of 198 subjects, was selected to evaluate Alzheimer\u0026rsquo;s disease-related Tau biomarkers. For each participant, two 200-\u0026micro;L K2EDTA plasma aliquots were sent to Quanterix, Billerica, MA, USA, for duplicate measurement of plasma pTau217 and BD-tau.\u003c/p\u003e\n\u003cp\u003ePlasma pTau217 was measured using the LucentAD p217 test, a laboratory-developed test based on the research-use-only Janssen plasma p217+Tau assay \u003csup\u003e29,30\u003c/sup\u003e. Additional analytical and clinical validation details for the LucentAD p217 assay have been described previously \u003csup\u003e31\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eBD-tau was measured using a Janssen-designed assay using Janssen mAb hT43 as the capture antibody and Janssen mAb pT82 as the detector antibody.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGenotyping\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGenomic DNA was extracted from whole blood samples from PD participants. Apolipoprotein E (APOE) genotyping was performed using allele-specific oligonucleotide probes labeled with a fluorogenic reporter using the TaqMan method \u003csup\u003e32\u003c/sup\u003e. Participants were classified as APOE \u0026epsilon;4 carriers or non-carriers according to the presence or absence of at least one \u0026epsilon;4 allele.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor statistical analysis, the programming language R, version 4.4.1, was utilized. The normality distribution assumption was tested with Shapiro-Wilk tests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNormally distributed continuous variables were summarized as mean \u0026plusmn; SD, whereas non-normally distributed variables were summarized as median and interquartile range. Categorical variables were summarized as number and percentage.\u003c/p\u003e\n\u003cp\u003eWe used the Kruskal-Wallis test or one-way ANOVA to compare continuous variables across the PD subgroups, and Pearson\u0026rsquo;s chi-square test was used to compare categorical variables.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe also compared plasma biomarker levels (pTau217 and BD-tau) using the Kruskal-Wallis test between PD subgroups, followed by a Bonferroni-corrected post hoc test to reduce the risk of inflated type I error due to multiple pairwise comparisons. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAssociations between plasma biomarkers and MoCA scores at baseline were examined using linear regression models that adjusted for age, sex, and education. For associations with longitudinal MoCA scores, we first derived individual slopes of MoCA scores in the PPMI study using linear mixed-effects models, which included longitudinal MoCA scores as the outcome and time (in years since baseline) as predictors, with random slopes and intercepts. Similarly, associations between baseline levels of pTau217 and BD-tau with MoCA slopes were tested using linear regression models adjusting for age, sex, and education. In the regression analysis, plasma biomarker measures were log10-transformed to better fit the normal distribution.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor the exploratory MCI-to-dementia conversion analysis, patients with baseline PD-MCI were classified as MCI-stable or MCI-converter according to whether they progressed to MoCA-defined dementia-level cognitive impairment during follow-up. Between-group comparisons were performed using the t-test or Wilcoxon rank-sum test based on normality distribution and Pearson\u0026rsquo;s chi-square test for categorical variables.\u003c/p\u003e\n\u003cp\u003eThe discriminative accuracies of plasma biomarkers between groups were assessed using receiver operating characteristic (ROC) curve analysis. The area under the curve (AUC), 95% confidence interval, sensitivity, and specificity were reported. Data-derived thresholds were estimated by maximizing Youden\u0026rsquo;s index\u003c/p\u003e\n\u003cp\u003eAll statistical tests were two-sided, and P \u0026lt;0.05 was considered statistically significant. Exact P values are reported wherever possible. Analyses were performed using available cases for each model, and missing values are reported in table footnotes\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e: The PPMI study was approved by the institutional review boards or ethics committees at all participating sites. All participants provided written informed consent before enrollment. The present analysis used de-identified data obtained from the PPMI database. All methods were performed in accordance with the relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: The authors disclose no financial, personal, or institutional conflicts of interest related to this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This study was carried out without any funding or financial support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions:\u0026nbsp;\u003c/strong\u003eEK conceptualized and designed the study, collected and curated the data, performed the statistical analyses, prepared the figures, drafted the initial manuscript, and revised the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUse of artificial intelligence-assisted tools\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring manuscript preparation, the author used ChatGPT to assist with language editing, structural refinement, and readability improvement. The author reviewed and edited all AI-assisted text and takes full responsibility for the content, accuracy, interpretation, and integrity of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: Parkinson’s Progression Markers Initiative (a public–private partnership) is funded by the Michael J Fox Foundation for Parkinson’s Research and funding partners, including AbbVie, Allergan, Avid Radiopharmaceuticals, Biogen, BioLegend, Bristol-Myers Squibb, Celgene, Denali, GE Healthcare, Genentech, GlaxoSmithKline, Lilly, Lundbeck, Merck, Meso Scale Discovery, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, Verily, Voyager Therapeutics, and Golub Capital. Data used in the preparation of this article were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). For up-to-date information on the study, visit\u0026nbsp;www.ppmi-info.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The datasets used and/or analyzed during the current study are available from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data).\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSchapira, A. H., Chaudhuri, K. R. \u0026amp; Jenner, P. Non-motor features of Parkinson disease. \u003cem\u003eNat. Rev. Neurosci.\u003c/em\u003e \u003cb\u003e18\u003c/b\u003e, 435\u0026ndash;450 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaiano, C., Barone, P., Trojano, L. \u0026amp; Santangelo, G. Prevalence and clinical aspects of mild cognitive impairment in Parkinson's disease: A meta-analysis. \u003cem\u003eMov. 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CSF biomarkers associated with disease heterogeneity in early Parkinson\u0026rsquo;s disease: the Parkinson\u0026rsquo;s Progression Markers Initiative study. \u003cem\u003eActa Neuropathol.\u003c/em\u003e \u003cb\u003e131\u003c/b\u003e, 935\u0026ndash;949 (2016).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Parkinson’s disease, pTau217, plasma biomarker, cognitive impairment, dementia, brain-derived tau","lastPublishedDoi":"10.21203/rs.3.rs-9606462/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9606462/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCognitive impairment is a major non-motor complication of Parkinson\u0026rsquo;s disease (PD), but accessible blood-based biomarkers associated with cognitive disfunction remain limited. This study investigated whether plasma phosphorylated tau at threonine 217 (pTau217) is associated with cognitive impairment and longitudinal cognitive decline in PD. Data from the Parkinson\u0026rsquo;s Progression Markers Initiative (PPMI) included 165 patients with PD with available baseline plasma pTau217 measurements. Cognitive status was classified using Montreal Cognitive Assessment (MoCA)-based criteria as normal cognition, mild cognitive impairment (MCI), or dementia-level cognitive impairment. Plasma pTau217 differed significantly across cognitive groups (P\u0026thinsp;=\u0026thinsp;0.007) and was higher in patients with dementia-level cognitive impairment than in cognitively normal patients. Higher baseline plasma pTau217 was associated with lower baseline MoCA score after adjustment for age, sex, and education (β = \u0026minus;2.683, P\u0026thinsp;=\u0026thinsp;0.009) and with greater longitudinal MoCA decline (β = \u0026minus;0.312, P\u0026thinsp;=\u0026thinsp;0.026). Brain-derived tau (BD-tau) was not consistently associated with cognitive outcomes. In patients with MCI, baseline plasma pTau217 showed moderate discrimination for subsequent dementia conversion (area under the curve [AUC]\u0026thinsp;=\u0026thinsp;0.731). These findings support plasma pTau217 as a promising blood-based marker associated with cognitive decline in PD, although validation in larger cohorts is needed.\u003c/p\u003e","manuscriptTitle":"“Plasma pTau217 is associated with cognitive impairment and longitudinal cognitive decline in Parkinson’s disease”","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-12 14:31:34","doi":"10.21203/rs.3.rs-9606462/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e37e0545-95f8-4b5f-aed5-594f5e930a5e","owner":[],"postedDate":"May 12th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvited","content":"","date":"2026-05-11T15:09:28+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-05-07T03:45:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-05-06T19:49:17+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":67944930,"name":"Health sciences/Biomarkers"},{"id":67944931,"name":"Health sciences/Diseases"},{"id":67944932,"name":"Health sciences/Neurology"},{"id":67944933,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2026-05-12T14:31:34+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-12 14:31:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9606462","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9606462","identity":"rs-9606462","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}