Portelius Erik, Zetterberg Henrik, Skillbäck Tobias, Törnqvist Ulrika, Andreasson Ulf, Trojanowski John Q, Weiner Michael W, Shaw Leslie M, Mattsson Niklas, Blennow Kaj
1 Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
1 Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden 2 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
Brain. 2015 Nov;138(Pt 11):3373-85. doi: 10.1093/brain/awv267. Epub 2015 Sep 15.
Synaptic dysfunction is linked to cognitive symptoms in Alzheimer's disease. Thus, measurement of synapse proteins in cerebrospinal fluid may be useful biomarkers to monitor synaptic degeneration. Cerebrospinal fluid levels of the postsynaptic protein neurogranin are increased in Alzheimer's disease, including in the predementia stage of the disease. Here, we tested the performance of cerebrospinal fluid neurogranin to predict cognitive decline and brain injury in the Alzheimer's Disease Neuroimaging Initiative study. An in-house immunoassay was used to analyse neurogranin in cerebrospinal fluid samples from a cohort of patients who at recruitment were diagnosed as having Alzheimer's disease with dementia (n = 95) or mild cognitive impairment (n = 173), as well as in cognitively normal subjects (n = 110). Patients with mild cognitive impairment were grouped into those that remained cognitively stable for at least 2 years (stable mild cognitive impairment) and those who progressed to Alzheimer's disease dementia during follow-up (progressive mild cognitive impairment). Correlations were tested between baseline cerebrospinal fluid neurogranin levels and baseline and longitudinal cognitive impairment, brain atrophy and glucose metabolism within each diagnostic group. Cerebrospinal fluid neurogranin was increased in patients with Alzheimer's disease dementia (P < 0.001), progressive mild cognitive impairment (P < 0.001) and stable mild cognitive impairment (P < 0.05) compared with controls, and in Alzheimer's disease dementia (P < 0.01) and progressive mild cognitive impairment (P < 0.05) compared with stable mild cognitive impairment. In the mild cognitive impairment group, high baseline cerebrospinal fluid neurogranin levels predicted cognitive decline as reflected by decreased Mini-Mental State Examination (P < 0.001) and increased Alzheimer's Disease Assessment Scale-cognitive subscale (P < 0.001) scores at clinical follow-up. In addition, high baseline cerebrospinal fluid neurogranin levels in the mild cognitive impairment group correlated with longitudinal reductions in cortical glucose metabolism (P < 0.001) and hippocampal volume (P < 0.001) at clinical follow-up. Furthermore, within the progressive mild cognitive impairment group, elevated cerebrospinal fluid neurogranin levels were associated with accelerated deterioration in Alzheimer's Disease Assessment Scale-cognitive subscale (β = 0.0017, P = 0.01). These data demonstrate that cerebrospinal fluid neurogranin is increased already at the early clinical stage of Alzheimer's disease and predicts cognitive deterioration and disease-associated changes in metabolic and structural biomarkers over time.
突触功能障碍与阿尔茨海默病的认知症状有关。因此，测量脑脊液中的突触蛋白可能是监测突触退化的有用生物标志物。阿尔茨海默病患者，包括疾病的痴呆前期阶段，脑脊液中突触后蛋白神经颗粒素的水平会升高。在此，我们在阿尔茨海默病神经影像学倡议研究中测试了脑脊液神经颗粒素预测认知衰退和脑损伤的性能。使用一种内部免疫测定法分析了一组患者脑脊液样本中的神经颗粒素，这些患者在招募时被诊断为患有阿尔茨海默病痴呆（n = 95）或轻度认知障碍（n = 173），以及认知正常的受试者（n = 110）。轻度认知障碍患者被分为至少2年保持认知稳定的患者（稳定型轻度认知障碍）和随访期间进展为阿尔茨海默病痴呆的患者（进展型轻度认知障碍）。在每个诊断组中，测试了基线脑脊液神经颗粒素水平与基线及纵向认知障碍、脑萎缩和葡萄糖代谢之间的相关性。与对照组相比，阿尔茨海默病痴呆患者（P < 0.001）、进展型轻度认知障碍患者（P < 0.001）和稳定型轻度认知障碍患者（P < 0.05）的脑脊液神经颗粒素水平升高，与稳定型轻度认知障碍相比，阿尔茨海默病痴呆患者（P < 0.01）和进展型轻度认知障碍患者（P < 0.05）的脑脊液神经颗粒素水平升高。在轻度认知障碍组中，高基线脑脊液神经颗粒素水平预测了认知衰退，临床随访时简易精神状态检查得分降低（P < 0.001）和阿尔茨海默病评估量表认知子量表得分升高（P < 0.001）反映了这一点。此外，轻度认知障碍组中高基线脑脊液神经颗粒素水平与临床随访时皮质葡萄糖代谢的纵向降低（P < 0.001）和海马体积的纵向降低（P < 0.001）相关。此外，在进展型轻度认知障碍组中，脑脊液神经颗粒素水平升高与阿尔茨海默病评估量表认知子量表的加速恶化相关（β = 0.0017，P = 0.01）。这些数据表明，脑脊液神经颗粒素在阿尔茨海默病的临床早期就已升高，并预测随着时间推移认知恶化以及代谢和结构生物标志物中与疾病相关的变化。
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