Evolution of Alzheimer's Disease Cerebrospinal Fluid Biomarkers in Early Parkinson's Disease

David J Irwin¹, Janel Fedler², Christopher S Coffey², Chelsea Caspell-Garcia², Ju Hee Kang³, Tanya Simuni⁴, Tatiana Foroud⁵, Arthur W Toga⁶, Caroline M Tanner⁷, Karl Kieburtz⁸, Lana M Chahine⁹, Alyssa Reimer¹⁰, Samantha Hutten¹⁰, Daniel Weintraub^{1

11

12}, Brit Mollenhauer¹³, Douglas R Galasko¹⁴, Andrew Siderowf¹, Kenneth Marek¹⁵, John Q Trojanowski^{16

17}, Leslie M Shaw¹⁶; Parkinson's Progression Marker Initiative

Affiliations

¹ Department of Neurology, School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
² Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, USA.
³ Department of Pharmacology & Clinical Pharmacology, Inha University, Incheon, South Korea.
⁴ Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁵ Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA.
⁶ Laboratory of Neuro Imaging, University of Southern California, Los Angeles, CA, USA.
⁷ Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
⁸ Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA.
⁹ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁰ The Michael J. Fox Foundation, New York, NY, USA.
¹¹ Department of Psychiatry Perelman, School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
¹² Michael J. Crescenz VA Medical Center, Parkinson's Disease Research, Education, and Clinical Center, Philadelphia, PA, USA.
¹³ Department of Neurology, University Medical Center, Göttingen Paracelsus-Elena-Klinik, Kassel, Germany.
¹⁴ Department of Neurology, University of San Diego, San Diego, CA, USA.
¹⁵ Institute for Neurodegenerative Disorders, New Haven, CT, USA.
¹⁶ Department of Pathology and Laboratory Medicine, School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
¹⁷ Center for Neurodegenerative Disease Research, School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

PMID: 32542885
PMCID: PMC7497251
DOI: 10.1002/ana.25811

Observational Study

Evolution of Alzheimer's Disease Cerebrospinal Fluid Biomarkers in Early Parkinson's Disease

David J Irwin et al. Ann Neurol. 2020 Sep.

. 2020 Sep;88(3):574-587.

doi: 10.1002/ana.25811. Epub 2020 Jul 2.

Authors

Affiliations

¹ Department of Neurology, School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
² Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, USA.
³ Department of Pharmacology & Clinical Pharmacology, Inha University, Incheon, South Korea.
⁴ Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁵ Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA.
⁶ Laboratory of Neuro Imaging, University of Southern California, Los Angeles, CA, USA.
⁷ Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
⁸ Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA.
⁹ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁰ The Michael J. Fox Foundation, New York, NY, USA.
¹¹ Department of Psychiatry Perelman, School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
¹² Michael J. Crescenz VA Medical Center, Parkinson's Disease Research, Education, and Clinical Center, Philadelphia, PA, USA.
¹³ Department of Neurology, University Medical Center, Göttingen Paracelsus-Elena-Klinik, Kassel, Germany.
¹⁴ Department of Neurology, University of San Diego, San Diego, CA, USA.
¹⁵ Institute for Neurodegenerative Disorders, New Haven, CT, USA.
¹⁶ Department of Pathology and Laboratory Medicine, School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
¹⁷ Center for Neurodegenerative Disease Research, School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

PMID: 32542885
PMCID: PMC7497251
DOI: 10.1002/ana.25811

Abstract

Objective: We analyzed the longitudinal profile of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in early Parkinson's disease (PD) compared with healthy controls (HCs) and tested baseline CSF biomarkers for prediction of clinical decline in PD.

Methods: Amyloid-β 1 to 42 (Aβ₄₂ ), total tau (t-tau) and phosphorylated tau (p-tau) at the threonine 181 position were measured using the high-precision Roche Elecsys electrochemiluminescence immunoassay in all available CSF samples from longitudinally studied patients with PD (n = 416) and HCs (n = 192) followed for up to 3 years in the Parkinson's Progression Markers Initiative (PPMI). Longitudinal CSF and clinical data were analyzed with linear-mixed effects models.

Results: We found patients with PD had lower CSF t-tau (median = 157.7 pg/mL; range = 80.9-467.0); p-tau (median = 13.4 pg/mL; range = 8.0-40.1), and Aβ₄₂ (median = 846.2 pg/mL; range = 238.8-3,707.0) than HCs at baseline (CSF t-tau median = 173.5 pg/mL; range = 82.0-580.8; p-tau median = 15.4 pg/mL; range = 8.1-73.6; and Aβ₄₂ median = 926.5 pg/mL; range = 239.1-3,297.0; p < 0.05-0.001) and a moderate-to-strong correlation among these biomarkers in both patients with PD and HCs (Rho = 0.50-0.97; p < 0.001). Of the patients with PD, 31.5% had pathologically low levels of CSF Aβ₄₂ at baseline and these patients with PD had lower p-tau levels (median = 10.8 pg/mL; range = 8.0-32.8) compared with 27.7% of HCs with pathologically low CSF Aβ₄₂ (CSF p-tau median = 12.8 pg/mL; range 8.2-73.6; p < 0.03)_. In longitudinal CSF analysis, we found patients with PD had greater decline in CSF Aβ₄₂ (mean difference = -41.83 pg/mL; p = 0.03) and CSF p-tau (mean difference = -0.38 pg/mL; p = 0.03) at year 3 compared with HCs. Baseline CSF Aβ₄₂ values predicted small but measurable decline on cognitive, autonomic, and motor function in early PD.

Interpretation: Our data suggest baseline CSF AD biomarkers may have prognostic value in early PD and that the dynamic change of these markers, although modest over a 3-year period, suggest biomarker profiles in PD may deviate from healthy aging. ANN NEUROL 2020;88:574-587.

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Conflict of interest statement

Dr. Mollenhauer has received honoraria for consultancy from Roche, Biogen, UCB, and Sun Pharma Advanced Research Company. Dr. Kieburtz reports other from Clintrex Research Corp., other from Hoover Brown LLC, outside the submitted work; Dr. Galasko reports personal fees from Biogen, Inc., personal fees from vTv Pharmaceuticals, Inc., personal fees from Fujirebio, Inc., personal fees from Cognition Therapeutics, outside the submitted work. Dr. Simuni reports grants from Biogen, Roche, Neuroderm, Sanofi, Sun Pharma, Abbvie, IMPAX, and Prevail, and other from Acadia, Abbvie, Accorda, Adamas, Allergan, Amneal, Aptinyx, Denali, General Electric (GE), Kyowa, Neuroderm, Neurocrine, Sanofi, Sinopia, Sunovion, Roche, Takeda, Voyager, and US World Meds, during the conduct of the study. Dr. Tanner reports grants from Gateway LLC, grants from Roche/Genentech, grants and personal fees from Biogen Idec, personal fees from Acorda, personal fees from Adamas Therapeutics, personal fees from Amneal, personal fees from CNS Ratings, personal fees from Grey Matter LLC, personal fees from Northwestern University, personal fees from Partners, Harvard U, outside the submitted work. Dr. Marek reports consulting from Michael J Fox, GE Healthcare, Takeda, Lundbeck, Neuron23, Roche, Neuroderm, and Invicro, outside the submitted work. PPMI is supported in part by Roche who manufacture the Elecsys assays used in the study.

Figures

**FIGURE 1**
Group‐wise comparison of baseline CSF biomarkers in PD and HC. Solid line represents group‐wise difference between patients with PD and HCs p < 0.05, solid line plus single asterisk p ≤ 0.01, and solid line plus double‐asterisk p < 0.001.

**FIGURE 2**
Baseline correlation of CSF biomarkers in patients with PD and HCs. Scatterplots depict individual patient datapoints for CSF values at baseline. Dashed‐line represents fitted line with 95% confidence interval. Red = patients with PD; and Blue = HCs.

**FIGURE 3**
Individual patient data for median change in AD CSF biomarker measurements at each timepoint. Spaghetti plot depicts individual‐patient trajectories (left panels) and trend lines (right panels) depict mean values for PD (red) and HC (blue) and 95% CI for mean change in biomarker value at each time point using LMM adjusted for age, sex, and the baseline value of the CSF outcome for mean change in measurements for CSF Aβ₄₂ (A) t‐tau (B) and p‐tau (C) at 6, 12, 24, and 36‐month timepoints. Across all timepoints we found a greater reduction in CSF Aβ₄₂ (mean difference −41.83 pg/mL; SE = 18.94; p = 0.03) and p‐tau (mean difference = −0.38 pg/mL; SE = 0.22; p = 0.03), in patients with PD compared to HCs with a nonsignificant trend for CSF t‐tau (mean difference = −3.7 pg/mL; SE = 2.7; p = 0.07).

See this image and copyright information in PMC

References

1. Irwin DJ, White MT, Toledo JB, et al. Neuropathologic substrates of Parkinson disease dementia. Ann Neurol 2012;72:587–598. - PMC - PubMed
1. Irwin DJ, Grossman M, Weintraub D, et al. Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis. Lancet Neurol 2017;16:55–65. - PMC - PubMed
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Evolution of Alzheimer's Disease Cerebrospinal Fluid Biomarkers in Early Parkinson's Disease

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Evolution of Alzheimer's Disease Cerebrospinal Fluid Biomarkers in Early Parkinson's Disease

Authors

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Conflict of interest statement

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