脑脊液 GAP-43 与淀粉样蛋白阳性个体认知下降速度及向痴呆进展的关系。
Association of CSF GAP-43 With the Rate of Cognitive Decline and Progression to Dementia in Amyloid-Positive Individuals.
机构信息
From the Department of Psychiatry and Neurochemistry (A.Ö., A.L.B., N.J.A., H.K., H.Z., K.B.), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal; Wallenberg Centre for Molecular and Translational Medicine (N.J.A.), University of Gothenburg, Sweden; Department of Old Age Psychiatry (N.J.A.), Institute of Psychiatry, Psychology and Neuroscience, King's College London; NIHR Biomedical Research Centre for Mental Health and Biomedical Research Unit for Dementia at South London and Maudsley NHS Foundation (N.J.A., H.Z.), London, United Kingdom; Clinical Neurochemistry Laboratory (H.K., K.B.), Sahlgrenska University Hospital, Mölndal, Sweden; Fujirebio Europe NV (M.V.), Ghent, Belgium; Department of Veterans Affairs Medical Center (M.W.W.), Center for Imaging of Neurodegenerative Diseases, San Francisco, CA; Departments of Radiology (M.W.W.), Medicine (M.W.W.), Psychiatry (M.W.W.) and Neurology (M.W.W.), University of California, San Francisco; Department of Pathology and Laboratory Medicine (J.Q.T., L.M.S.), Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia; Department of Neurodegenerative Disease (H.Z.), UCL Institute of Neurology, London, United Kingdom; UK Dementia Research Institute (H.Z.), London; and Hong Kong Center for Neurodegenerative Diseases (H.Z.), China.
出版信息
Neurology. 2023 Jan 17;100(3):e275-e285. doi: 10.1212/WNL.0000000000201417. Epub 2022 Oct 3.
BACKGROUND AND OBJECTIVES
To test the associations between the presynaptic growth-associated protein 43 (GAP-43), quantified in CSF, and biomarkers of Alzheimer disease (AD) pathophysiology, cross-sectionally and longitudinally.
METHODS
In this retrospective study, GAP-43 was measured in participants from the AD Neuroimaging Initiative (ADNI) cohort using an in-house ELISA method, and levels were compared between groups, both cross-sectionally and longitudinally. Linear regression models tested the associations between biomarkers of AD (amyloid beta [Aβ] and tau pathologies, neurodegeneration, and cognition) adjusted by age, sex, and diagnosis. Linear mixed-effect models evaluated how baseline GAP-43 predicts brain hypometabolism, atrophy, and cognitive decline over time. Cox proportional hazard regression models tested how GAP-43 levels and Aβ status, at baseline, increased the risk of progression to AD dementia over time.
RESULTS
This study included 786 participants from the ADNI cohort, which were further classified in cognitively unimpaired (CU) Aβ-negative (n = 197); CU Aβ-positive (n = 55), mild cognitively impaired (MCI) Aβ-negative (n = 228), MCI Aβ-positive (n = 193), and AD dementia Aβ-positive (n = 113). CSF GAP-43 levels were increased in Aβ-positive compared with Aβ-negative participants, independent of the cognitive status. In Aβ-positive participants, high baseline GAP-43 levels led to worse brain metabolic decline ( = 0.01), worse brain atrophy ( = 8.8 × 10), and worse MMSE scores ( = 0.03) over time, as compared with those with low GAP-43 levels. Similarly, Aβ-positive participants with high baseline GAP-43 had the highest risk to convert to AD dementia (hazard ratio [HR = 8.56, 95% CI 4.94-14.80, = 1.5 × 10]). Despite the significant association with Aβ pathology (η = 0.09, < 0.001), CSF total tau (tTau) and phosphorylated tau (pTau) had a larger effect size on GAP43 than Aβ PET (η = 0.53, < 0.001; η = 0.59, < 0.001).
DISCUSSION
High baseline levels of CSF GAP-43 are associated with progression in Aβ-positive individuals, with a more aggressive neurodegenerative process, faster rate of cognitive decline, and increased risk of converting to dementia.
背景与目的
本研究旨在测试脑脊液中突触前生长相关蛋白 43（GAP-43）与阿尔茨海默病（AD）病理生理学生物标志物之间的横断面和纵向关联。
方法
在这项回顾性研究中，我们使用内部 ELISA 方法测量了 AD 神经影像学倡议（ADNI）队列中参与者的 GAP-43 水平，并在横断面和纵向比较了不同组之间的水平。线性回归模型测试了 AD 生物标志物（β淀粉样蛋白[Aβ]和 tau 病理学、神经退行性变和认知）与年龄、性别和诊断调整后的关联。线性混合效应模型评估了基线 GAP-43 如何预测随时间的脑代谢低下、萎缩和认知下降。Cox 比例风险回归模型测试了基线时 GAP-43 水平和 Aβ 状态如何随时间增加向 AD 痴呆进展的风险。
结果
本研究纳入了 ADNI 队列的 786 名参与者，这些参与者进一步分为认知正常（CU）Aβ 阴性（n = 197）；CU Aβ 阳性（n = 55），轻度认知障碍（MCI）Aβ 阴性（n = 228），MCI Aβ 阳性（n = 193）和 AD 痴呆 Aβ 阳性（n = 113）。与 Aβ 阴性参与者相比，Aβ 阳性参与者的 CSF GAP-43 水平升高，且与认知状态无关。在 Aβ 阳性参与者中，与低 GAP-43 水平相比，基线时 GAP-43 水平较高的参与者脑代谢下降更严重（ = 0.01），脑萎缩更严重（ = 8.8 × 10），简易精神状态检查表（MMSE）评分更差（ = 0.03）。同样，基线时 GAP-43 水平较高的 Aβ 阳性参与者向 AD 痴呆转化的风险最高（危险比[HR] = 8.56，95%置信区间[CI] 4.94-14.80， = 1.5 × 10）。尽管与 Aβ 病理学有显著关联（η = 0.09， < 0.001），但 CSF 总 tau（tTau）和磷酸化 tau（pTau）对 GAP43 的影响大于 Aβ PET（η = 0.53， < 0.001；η = 0.59， < 0.001）。
讨论
基线 CSF GAP-43 水平较高与 Aβ 阳性个体的进展相关，表现为神经退行性变过程更具侵袭性，认知下降速度更快，向痴呆转化的风险增加。
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