A Longitudinal Study of Total and Phosphorylated α-Synuclein with Other Biomarkers in Cerebrospinal Fluid of Alzheimer’s Disease and Mild Cognitive Impairment

Article type: Research Article

Authors: Wang, Hua^{a; b; 1} | Stewart, Tessandra^{a; 1} | Toledo, Jon B.^c | Ginghina, Carmen^a | Tang, Lu^a | Atik, Anzari^a | Aro, Patrick^a | Shaw, Leslie M.^d | Trojanowski, John Q.^{c; d; e; f} | Galasko, Douglas R.^g | Edland, Steven^{g; h} | Jensen, Poul H.ⁱ | Shi, Min^a | Zhang, Jing^{a; b; *} | for The Alzheimer’s Disease Neuroimaging Initiative²

Affiliations: [a] Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA | [b] Department of Pathology, Peking University Health Science Centre and Third Hospital, Beijing, China | [c] Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA | [d] Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA | [e] Alzheimer’s Disease Core Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA | [f] Udall Parkinson’s Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA | [g] Department of Neurosciences, Shiley-Marcos Alzheimer’s Disease Research Center, University of California, San Diego, CA, USA | [h] Division of Biostatistics and Bioinformatics, University of California San Diego, San Diego, CA, USA | [i] University of Aarhus, DANDRITE—Danish Research Institute of Translational Neuroscience and Department of Biomedicine, Aarhus, Denmark

Correspondence: [*] Correspondence to: Jing Zhang, MD, PhD, Professor and Shaw Endowed Chair, UW Medicine Neuropathology, University of Washington School of Medicine, Seattle, WA, USA. Tel.: +1 206 897 5245; Fax: +1 206 897 5294; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Note: [2] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

Abstract: Alzheimer’s disease (AD) features a dynamic sequence of amyloid deposition, neurodegeneration, and cognitive impairment. A significant fraction of AD brains also displays Lewy body pathology, suggesting that addition of classically Parkinson’s disease-related proteins to the AD biomarker panel may be of value. To determine whether addition of cerebrospinal fluid (CSF) total α-synuclein and its form phosphorylated at S129 (pS129) to the AD biomarker panel [Amyloid-β1-42 (Aβ42), tau, and phosphorylated tau (p-tau181)] improves its performance, we examined CSF samples collected longitudinally up to 7 years as part of the Alzheimer’s Disease Neuroimaging Initiative. From 87 AD, 177 mild cognitive impairment (MCI), and 104 age-matched healthy controls, 792 baseline and longitudinal CSF samples were tested for total α-synuclein, pS129, Aβ42, tau, and p-tau181. pS129, but not total α-synuclein, was weakly associated with diagnosis at baseline when t-tau/Aβ42 was included in the statistical model (β= 0.0026, p = 0.041, 95% CI [(0.0001)–(0.005)]). CSF α-synuclein predicted Alzheimer’s Disease Assessment Scale-Cognitive (β= –0.59, p = 0.0015, 95% CI [(–0.96)–(–0.23)]), memory (β= 0.4, p = 0.00025, 95% CI [(0.16)–(0.59)]), and executive (0.62,<0.0001, 95% CI [(0.31)–(0.93)]) function composite scores, and progression from MCI to AD (β= 0.019, p = 0.0011, 95% CI [(0.002)–(0.20)]). pS129 was associated with executive function (β= –2.55, p = 0.0085, 95% CI [(–4.45)–(–0.66)]). Lower values in the mismatch between α-synuclein and p-tau181 predicted faster cognitive decline (β= 0.64, p = 0.0012, 95% CI [(0.48)–(0.84)]). Longitudinal biomarker changes did not differ between groups, and may not reflect AD progression. The α-synuclein-p-tau181-Mismatch could better predict longitudinal cognitive changes than classical AD markers alone, and its pathological correlates should be investigated further.

Keywords: α-synuclein, Alzheimer’s disease, biomarkers, cerebrospinal fluid, mild cognitive impairment, pS129-α-synuclein

DOI: 10.3233/JAD-171013

Journal: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1541-1553, 2018