评估 ATN 框架和生物流体标志物以预测早期帕金森病的认知下降。
Evaluation of ATN Framework and Biofluid Markers to Predict Cognitive Decline in Early Parkinson Disease.
机构信息
From the Department of Neurology (K.A.Q.C., D.J.I., T.F.T., E.R., J.P., A.S.C.-P., D.W.), University of Pennsylvania, Philadelphia; Department of Biostatistics (M.C.B., C.S.C.), College of Public Health, University of Iowa, Iowa City; Department of Pharmacology and Clinical Pharmacology (J.H.K.), Inha University, Incheon, South Korea; Feinberg School of Medicine (T.S.), Northwestern University, Chicago, IL; Department of Medical and Molecular Genetics (T.M.F.), Indiana University, Indianapolis; Laboratory of Neuro Imaging (A.W.T.), University of Southern California, Los Angeles; Department of Neurology (C.M.T.), Weill Institute for Neurosciences, University of California San Francisco; Department of Neurology (K.D.K.), University of Rochester Medical Center, NY; Department of Neurology (B.M.), University Medical Center, Göttingen, Paracelsus-Elena-Klinik, Germany; Department of Neurology (D.G.), University of California San Diego; The Michael J. Fox Foundation (S.H.), New York, NY; Department of Psychiatry (D.W.), School of Medicine at the University of Pennsylvania; Michael J. Crescenz VA Medical Center (D.W.), Parkinson's Disease Research, Education, and Clinical Center; Department of Neurology (A.D.S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Institute for Neurodegenerative Disorders (K.M.), New Haven, CT; Department of Neurology (K.L.P.), Stanford University, Palo Alto, CA; and Department of Pathology and Laboratory Medicine (L.M.S.), University of Pennsylvania, Philadelphia.
出版信息
Neurology. 2024 Feb;102(4):e208033. doi: 10.1212/WNL.0000000000208033. Epub 2024 Feb 2.
BACKGROUND AND OBJECTIVES
In Parkinson disease (PD), Alzheimer disease (AD) copathology is common and clinically relevant. However, the longitudinal progression of AD CSF biomarkers-β-amyloid 1-42 (Aβ), phosphorylated tau 181 (p-tau), and total tau (t-tau)-in PD is poorly understood and may be distinct from clinical AD. Moreover, it is unclear whether CSF p-tau and serum neurofilament light (NfL) have added prognostic utility in PD, when combined with CSF Aβ. First, we describe longitudinal trajectories of biofluid markers in PD. Second, we modified the AD β-amyloid/tau/neurodegeneration (ATN) framework for application in PD (ATN) using CSF Aβ (A), p-tau (T), and serum NfL (N) and tested ATN prediction of longitudinal cognitive decline in PD.
METHODS
Participants were selected from the Parkinson's Progression Markers Initiative cohort, clinically diagnosed with sporadic PD or as controls, and followed up annually for 5 years. Linear mixed-effects models (LMEMs) tested the interaction of diagnosis with longitudinal trajectories of analytes (log transformed, false discovery rate [FDR] corrected). In patients with PD, LMEMs tested how baseline ATN status (AD [A+T+N±] vs not) predicted clinical outcomes, including Montreal Cognitive Assessment (MoCA; rank transformed, FDR corrected).
RESULTS
Participants were 364 patients with PD and 168 controls, with comparable baseline mean (±SD) age (patients with PD = 62 ± 10 years; controls = 61 ± 11 years]; Mann-Whitney Wilcoxon: = 0.4) and sex distribution (patients with PD = 231 male individuals [63%]; controls = 107 male individuals [64%]; χ: = 1). Patients with PD had overall lower CSF p-tau (β = -0.16, 95% CI -0.23 to -0.092, = 2.2e-05) and t-tau than controls (β = -0.13, 95% CI -0.19 to -0.065, = 4e-04), but not Aβ ( = 0.061) or NfL ( = 0.32). Over time, patients with PD had greater increases in serum NfL than controls (β = 0.035, 95% CI 0.022 to 0.048, = 9.8e-07); slopes of patients with PD did not differ from those of controls for CSF Aβ ( = 0.18), p-tau ( = 1), or t-tau ( = 0.96). Using ATN, PD classified as A+T+N± (n = 32; 9%) had worse cognitive decline on global MoCA (β = -73, 95% CI -110 to -37, = 0.00077) than all other ATN statuses including A+ alone (A+T-N-; n = 75; 21%).
DISCUSSION
In patients with early PD, CSF p-tau and t-tau were low compared with those in controls and did not increase over 5 years of follow-up. Our study shows that classification using modified ATN (incorporating CSF Aβ, CSF p-tau, and serum NfL) can identify biologically relevant subgroups of PD to improve prediction of cognitive decline in early PD.
背景与目的
在帕金森病（PD）中，阿尔茨海默病（AD）共病较为常见且具有临床相关性。然而，PD 患者脑脊液 AD 生物标志物β-淀粉样蛋白 1-42（Aβ）、磷酸化 tau181（p-tau）和总 tau（t-tau）的纵向进展情况尚不清楚，且可能与临床 AD 不同。此外，当与 CSF Aβ 联合使用时，CSF p-tau 和血清神经丝轻链（NfL）是否在 PD 中具有额外的预后价值，目前尚不清楚。首先，我们描述了 PD 患者生物流体标志物的纵向轨迹。其次，我们修改了 AD β-淀粉样蛋白/tau/神经退行性变（ATN）框架，用于 PD（ATN）的应用（Aβ、p-tau 和血清 NfL），并在 PD 患者中测试了 ATN 对纵向认知下降的预测作用。
方法
参与者从帕金森进展标志物倡议队列中选择，临床诊断为散发性 PD 或作为对照，每年随访 5 年。线性混合效应模型（LMEM）测试了诊断与分析物纵向轨迹之间的相互作用（对数转换，错误发现率[FDR]校正）。在 PD 患者中，LMEM 测试了基线 ATN 状态（AD[A+T+N±]或非 AD）如何预测临床结局，包括蒙特利尔认知评估（MoCA；秩转换，FDR 校正）。
结果
参与者为 364 例 PD 患者和 168 例对照，基线平均（±SD）年龄（PD 患者=62±10 岁；对照组=61±11 岁）相似（Mann-Whitney Wilcoxon：=0.4），性别分布也相似（PD 患者 231 例男性[63%]；对照组 107 例男性[64%]；χ：=1）。与对照组相比，PD 患者的总体 CSF p-tau（β=-0.16，95%CI-0.23 至-0.092，=2.2e-05）和 t-tau 较低（β=-0.13，95%CI-0.19 至-0.065，=4e-04），但 Aβ（=0.061）或 NfL（=0.32）则不然。随着时间的推移，PD 患者血清 NfL 的增加速度快于对照组（β=0.035，95%CI 0.022 至 0.048，=9.8e-07）；PD 患者的 CSF Aβ（=0.18）、p-tau（=1）或 t-tau（=0.96）的斜率与对照组无差异。使用 ATN，PD 分类为 A+T+N±（n=32；9%）的患者在全球 MoCA 上的认知下降更为严重（β=-73，95%CI-110 至-37，=0.00077），而非其他所有 ATN 状态，包括 A+ alone（A+T-N-；n=75；21%）。
讨论
在早期 PD 患者中，CSF p-tau 和 t-tau 与对照组相比较低，且在 5 年的随访中并未增加。我们的研究表明，使用改良的 ATN（包含 CSF Aβ、CSF p-tau 和血清 NfL）进行分类可以识别 PD 的生物学相关亚组，从而改善早期 PD 患者认知下降的预测。
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