Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer's disease

被引:155
作者
Portelius, Erik [1 ]
Zetterberg, Henrik [1 ,2 ]
Skillback, Tobias [1 ]
Tornqvist, Ulrika [1 ]
Andreasson, Ulf [1 ]
Trojanowski, John Q. [3 ]
Weiner, Michael W. [4 ,5 ]
Shaw, Leslie M. [3 ]
Mattsson, Niklas [6 ]
Blennow, Kaj [7 ]
机构
[1] Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, Inst Neurosci & Physiol, Molndal, Sweden
[2] UCL Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England
[3] Univ Penn, Sch Med, Ctr Neurodegenerat Dis Res, Dept Pathol & Lab Med,Inst Aging, Philadelphia, PA 19104 USA
[4] Univ Calif San Francisco, Ctr Imaging Neurodegenerat Dis, Dept Vet Affairs Med Ctr, San Francisco, CA 94143 USA
[5] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94143 USA
[6] Lund Univ, Clin Memory Res Unit, S-22100 Lund, Sweden
[7] Royal Swedish Acad Sci, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Med, Molndal, Sweden
基金
瑞典研究理事会; 加拿大健康研究院; 美国国家卫生研究院;
关键词
Alzheimer's disease; neurogranin; cerebrospinal fluid; biomarker; mild cognitive impairment; KINASE-C SUBSTRATE; LONG-TERM POTENTIATION; SYNAPTIC PLASTICITY; VESICLE PROTEIN; BRAIN; CORTEX; CALCIUM/CALMODULIN; IDENTIFICATION; THRESHOLD; PATHOLOGY;
D O I
10.1093/brain/awv267
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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 (P50.05) compared with controls, and in Alzheimer's disease dementia (P < 0.01) and progressive mild cognitive impairment (P50.05) 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 (beta = 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.
引用
收藏
页码:3373 / 3385
页数:13
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